Dermatopathology

To the Editor:

Dermatofibroma is a common cutaneous lesion that most frequently affects young or middle-aged adults, especially women.¹ Clinically, it appears as a firm, pink or brown nodule. It may be painful or show a tendency for scarring. The pathognomonic feature of dermatofibroma, regarded as a fibrohistiocytic tumor, is the so-called button sign caused by skin depression following pressure. We present a unique case of elongated dermatofibroma with a linear, white, scarlike patch with a brownish pigmented network and globules.

A 40-year-old woman presented with a linear elongated lesion localized to the right side of the infrascapular region of 10 years’ duration. The lesion initially was a small brownish plaque. There was no history of trauma or scratching. Over the next 10 years, the lesion slowly progressed, finally becoming a linear, atrophic, brownish plaque that was 2.5-cm long (Figure 1). The button sign was positive. On dermoscopy the central, elongated, white patch was visualized not as a typical round patch but as a scarlike white line (Figure 2A) surrounded by a brownish network that was especially pronounced in the distal parts of the lesion. In the upper part of the lesion, multiple marginally disseminated, dark brown dots were present. Brownish globules within the linear white patch also were observed in the lower central part. Figure 2B presents a dermoscopic picture of the linear variant of dermatofibroma. For cosmetic reasons, the patient underwent total surgical excision of the lesion. Histopathology revealed distinct characteristics of dermatofibroma (Figures 3A and 3B).

The most common features of dermatofibromas seen in polarized and nonpolarized dermoscopy are central white scarlike patches, brown globulelike structures, vascular structures, and a peripheral fine pigmented network.² Kilinc Karaarslan et al³ described atypical dermatofibromas with linear irregular crypts, which were seen in 26.9% of all studied cases. These irregular crypts were mainly medium in size (10 lesions), with only 2 lesions being tiny and regularly distributed. Only one lesion had atypical clinical and dermoscopic features occurring as an atrophic plaque with multiple small scarlike areas and peripherally distributed pigment network.³ Based on this typology, we believe our patient represents a case of elongated dermatofibroma that could be an atrophic variant of dermatofibroma. This form would not appear as a small scarlike area with pigment network in a somewhat patchy distribution³ but as a scarlike linear chord with a bipolar pigment network. Zaballos et al¹ described 10 dermoscopic patterns of dermatofibroma (N=412); the most common was a central white patch and peripheral pigment network in approximately 35% of cases. A white scarlike patch was observed in 57.0% of dermat-ofibromas in 4 variants: (1) a solitary structure located in the center; (2) multiple white scarlike patches; (3) white scarlike patch extending throughout the lesion or irregularly distributed; and (4) white network (central, total, or irregular).¹ Agero et al² first described the new feature as a central white patch characterized by shiny white streaks. The most frequent dermoscopic pattern associated with dermatofibromas is the central white scarlike patch and peripheral delicate pigment network.^1,4 Arpaia et al⁴ observed that dermoscopic patterns may correspond to distinct sequential stages of the formation of dermatofibroma. The linear character we described may be related to a variant of scarring keloid dermatofibroma.⁵

To the Editor:

Dermatofibroma is a common cutaneous lesion that most frequently affects young or middle-aged adults, especially women.¹ Clinically, it appears as a firm, pink or brown nodule. It may be painful or show a tendency for scarring. The pathognomonic feature of dermatofibroma, regarded as a fibrohistiocytic tumor, is the so-called button sign caused by skin depression following pressure. We present a unique case of elongated dermatofibroma with a linear, white, scarlike patch with a brownish pigmented network and globules.

A 40-year-old woman presented with a linear elongated lesion localized to the right side of the infrascapular region of 10 years’ duration. The lesion initially was a small brownish plaque. There was no history of trauma or scratching. Over the next 10 years, the lesion slowly progressed, finally becoming a linear, atrophic, brownish plaque that was 2.5-cm long (Figure 1). The button sign was positive. On dermoscopy the central, elongated, white patch was visualized not as a typical round patch but as a scarlike white line (Figure 2A) surrounded by a brownish network that was especially pronounced in the distal parts of the lesion. In the upper part of the lesion, multiple marginally disseminated, dark brown dots were present. Brownish globules within the linear white patch also were observed in the lower central part. Figure 2B presents a dermoscopic picture of the linear variant of dermatofibroma. For cosmetic reasons, the patient underwent total surgical excision of the lesion. Histopathology revealed distinct characteristics of dermatofibroma (Figures 3A and 3B).

The most common features of dermatofibromas seen in polarized and nonpolarized dermoscopy are central white scarlike patches, brown globulelike structures, vascular structures, and a peripheral fine pigmented network.² Kilinc Karaarslan et al³ described atypical dermatofibromas with linear irregular crypts, which were seen in 26.9% of all studied cases. These irregular crypts were mainly medium in size (10 lesions), with only 2 lesions being tiny and regularly distributed. Only one lesion had atypical clinical and dermoscopic features occurring as an atrophic plaque with multiple small scarlike areas and peripherally distributed pigment network.³ Based on this typology, we believe our patient represents a case of elongated dermatofibroma that could be an atrophic variant of dermatofibroma. This form would not appear as a small scarlike area with pigment network in a somewhat patchy distribution³ but as a scarlike linear chord with a bipolar pigment network. Zaballos et al¹ described 10 dermoscopic patterns of dermatofibroma (N=412); the most common was a central white patch and peripheral pigment network in approximately 35% of cases. A white scarlike patch was observed in 57.0% of dermat-ofibromas in 4 variants: (1) a solitary structure located in the center; (2) multiple white scarlike patches; (3) white scarlike patch extending throughout the lesion or irregularly distributed; and (4) white network (central, total, or irregular).¹ Agero et al² first described the new feature as a central white patch characterized by shiny white streaks. The most frequent dermoscopic pattern associated with dermatofibromas is the central white scarlike patch and peripheral delicate pigment network.^1,4 Arpaia et al⁴ observed that dermoscopic patterns may correspond to distinct sequential stages of the formation of dermatofibroma. The linear character we described may be related to a variant of scarring keloid dermatofibroma.⁵

To the Editor:

Dermatofibroma is a common cutaneous lesion that most frequently affects young or middle-aged adults, especially women.¹ Clinically, it appears as a firm, pink or brown nodule. It may be painful or show a tendency for scarring. The pathognomonic feature of dermatofibroma, regarded as a fibrohistiocytic tumor, is the so-called button sign caused by skin depression following pressure. We present a unique case of elongated dermatofibroma with a linear, white, scarlike patch with a brownish pigmented network and globules.

A 40-year-old woman presented with a linear elongated lesion localized to the right side of the infrascapular region of 10 years’ duration. The lesion initially was a small brownish plaque. There was no history of trauma or scratching. Over the next 10 years, the lesion slowly progressed, finally becoming a linear, atrophic, brownish plaque that was 2.5-cm long (Figure 1). The button sign was positive. On dermoscopy the central, elongated, white patch was visualized not as a typical round patch but as a scarlike white line (Figure 2A) surrounded by a brownish network that was especially pronounced in the distal parts of the lesion. In the upper part of the lesion, multiple marginally disseminated, dark brown dots were present. Brownish globules within the linear white patch also were observed in the lower central part. Figure 2B presents a dermoscopic picture of the linear variant of dermatofibroma. For cosmetic reasons, the patient underwent total surgical excision of the lesion. Histopathology revealed distinct characteristics of dermatofibroma (Figures 3A and 3B).

The most common features of dermatofibromas seen in polarized and nonpolarized dermoscopy are central white scarlike patches, brown globulelike structures, vascular structures, and a peripheral fine pigmented network.² Kilinc Karaarslan et al³ described atypical dermatofibromas with linear irregular crypts, which were seen in 26.9% of all studied cases. These irregular crypts were mainly medium in size (10 lesions), with only 2 lesions being tiny and regularly distributed. Only one lesion had atypical clinical and dermoscopic features occurring as an atrophic plaque with multiple small scarlike areas and peripherally distributed pigment network.³ Based on this typology, we believe our patient represents a case of elongated dermatofibroma that could be an atrophic variant of dermatofibroma. This form would not appear as a small scarlike area with pigment network in a somewhat patchy distribution³ but as a scarlike linear chord with a bipolar pigment network. Zaballos et al¹ described 10 dermoscopic patterns of dermatofibroma (N=412); the most common was a central white patch and peripheral pigment network in approximately 35% of cases. A white scarlike patch was observed in 57.0% of dermat-ofibromas in 4 variants: (1) a solitary structure located in the center; (2) multiple white scarlike patches; (3) white scarlike patch extending throughout the lesion or irregularly distributed; and (4) white network (central, total, or irregular).¹ Agero et al² first described the new feature as a central white patch characterized by shiny white streaks. The most frequent dermoscopic pattern associated with dermatofibromas is the central white scarlike patch and peripheral delicate pigment network.^1,4 Arpaia et al⁴ observed that dermoscopic patterns may correspond to distinct sequential stages of the formation of dermatofibroma. The linear character we described may be related to a variant of scarring keloid dermatofibroma.⁵

To the Editor:

A 71-year-old woman with hypertension and atrial fibrillation due to thyrotoxicosis was prescribed dabigatran for stroke prevention by her cardiologist. She also was taking pantoprazole, methimazole, and amiodarone at the time of presentation, all managed by her endocrinologist. She had no known drug allergies but reported a remote history of a palmar rash after eating shellfish. She otherwise had never had any problems with her skin and had no family history of psoriasis. She had a history of smoking 50 packs per year but had quit 6 months prior to presentation. After two 150-mg doses of dabigatran, she noticed numerous mildly tender and itchy eruptions on the palmar and plantar surfaces with no associated respiratory, oropharyngeal, or constitutional symptoms. She denied any recent shellfish ingestion. On dermatologic examination, numerous discreet pustules were present on the bilateral palmar and plantar surfaces with minimal erythema of the underlying skin (Figure).

A punch biopsy was taken from a newly forming lesion on the right palm. Histopathology revealed mild hyperkeratosis, spongiosis with lymphocyte exocytosis, intraepidermal vesiculation, and a sparse upper dermal and perivascular lymphohistiocytic infiltration. No neutrophils or microabscesses were seen. Staining with periodic acid–Schiff revealed no fungi, and S-100 staining revealed numerous Langerhans cells in the epidermis. Although the skin lesions clinically appeared pustular, the results were consistent with an eczematous drug reaction. Laboratory values, including a complete blood cell count, iron studies, chemistry panels, liver function, thyroid function, and coagulation studies, were remarkable only for mild anemia. The patient declined any topical or systemic skin treatment. Dabigatran was discontinued, and the lesions began to clear immediately thereafter. Dabigatran was not reintroduced. Enoxaparin subsequently was prescribed for anticoagulation. The diagnosis of a drug reaction due to dabigatran was made, which was supported with a score of 7 on the Naranjo scale (0=doubtful; 1–4=possible; 5–8=probable; ≥9=definite) for determining probability of drug-induced adverse reactions.¹ The differential diagnosis for the skin eruption included palmoplantar pustular psoriasis, dyshidrotic eczema, and allergic contact dermatitis, but the clinical history did not support these diagnoses.

Dabigatran is a direct thrombin inhibitor used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Based on results of the RE-LY (Randomization Evaluation of Long-term Anticoagulation Therapy) trial published in 2009, dabigatran 150 mg twice daily significantly reduced the risk for stroke and systemic emboli in patients with atrial fibrillation compared to warfarin (annual risk, 1.11% vs 1.69%; relative risk, 0.66; 95% CI, 0.53-0.82; P<.001) with the advantage of not requiring frequent monitoring of the international normalized ratio.² The most common adverse effect of dabigatran in this trial was dyspepsia (11.3% vs 5.8%). Drug hypersensitivity, allergic edema, and anaphylaxis were reported in less than 0.1% of patients taking dabigatran.²

According to a PubMed search of articles indexed for MEDLINE using the search terms dabigatran cutaneous reaction and dabigatran rash, 4 case reports of cutaneous eruption due to dabigatran were identified. In one report, a 20-year-old man with atrial fibrillation developed an eruption similar to our patient on the thigh and forearm after 2 weeks of taking oral dabigatran 150 mg twice daily. It resolved without complication after topical corticosteroid use and discontinuation of dabigatran.³ In another report, a 78-year-old man presented to the emergency department after taking two 150-mg doses of dabigatran with a diffuse, full-body, pruritic rash that resolved with oral diphenhydramine and discontinuation of dabigatran.⁴ A third case described a 59-year-old man who was taking 150 mg dabigatran twice daily for 5 days before developing a rash.⁵ The fourth case involved a 74-year-old woman who developed leukocytoclastic vasculitis 1 week after taking dabigatran 150 mg twice daily.⁶

It is important to monitor for and report hypersensitivity reactions in patients taking dabigatran. Drug exanthems may cause discomfort or even herald more serious hypersensitivity reactions. Patients experiencing these reactions may discontinue therapy without notifying a physician and consequently place themselves at risk for embolism or stroke.

To the Editor:

A 71-year-old woman with hypertension and atrial fibrillation due to thyrotoxicosis was prescribed dabigatran for stroke prevention by her cardiologist. She also was taking pantoprazole, methimazole, and amiodarone at the time of presentation, all managed by her endocrinologist. She had no known drug allergies but reported a remote history of a palmar rash after eating shellfish. She otherwise had never had any problems with her skin and had no family history of psoriasis. She had a history of smoking 50 packs per year but had quit 6 months prior to presentation. After two 150-mg doses of dabigatran, she noticed numerous mildly tender and itchy eruptions on the palmar and plantar surfaces with no associated respiratory, oropharyngeal, or constitutional symptoms. She denied any recent shellfish ingestion. On dermatologic examination, numerous discreet pustules were present on the bilateral palmar and plantar surfaces with minimal erythema of the underlying skin (Figure).

A punch biopsy was taken from a newly forming lesion on the right palm. Histopathology revealed mild hyperkeratosis, spongiosis with lymphocyte exocytosis, intraepidermal vesiculation, and a sparse upper dermal and perivascular lymphohistiocytic infiltration. No neutrophils or microabscesses were seen. Staining with periodic acid–Schiff revealed no fungi, and S-100 staining revealed numerous Langerhans cells in the epidermis. Although the skin lesions clinically appeared pustular, the results were consistent with an eczematous drug reaction. Laboratory values, including a complete blood cell count, iron studies, chemistry panels, liver function, thyroid function, and coagulation studies, were remarkable only for mild anemia. The patient declined any topical or systemic skin treatment. Dabigatran was discontinued, and the lesions began to clear immediately thereafter. Dabigatran was not reintroduced. Enoxaparin subsequently was prescribed for anticoagulation. The diagnosis of a drug reaction due to dabigatran was made, which was supported with a score of 7 on the Naranjo scale (0=doubtful; 1–4=possible; 5–8=probable; ≥9=definite) for determining probability of drug-induced adverse reactions.¹ The differential diagnosis for the skin eruption included palmoplantar pustular psoriasis, dyshidrotic eczema, and allergic contact dermatitis, but the clinical history did not support these diagnoses.

Dabigatran is a direct thrombin inhibitor used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Based on results of the RE-LY (Randomization Evaluation of Long-term Anticoagulation Therapy) trial published in 2009, dabigatran 150 mg twice daily significantly reduced the risk for stroke and systemic emboli in patients with atrial fibrillation compared to warfarin (annual risk, 1.11% vs 1.69%; relative risk, 0.66; 95% CI, 0.53-0.82; P<.001) with the advantage of not requiring frequent monitoring of the international normalized ratio.² The most common adverse effect of dabigatran in this trial was dyspepsia (11.3% vs 5.8%). Drug hypersensitivity, allergic edema, and anaphylaxis were reported in less than 0.1% of patients taking dabigatran.²

According to a PubMed search of articles indexed for MEDLINE using the search terms dabigatran cutaneous reaction and dabigatran rash, 4 case reports of cutaneous eruption due to dabigatran were identified. In one report, a 20-year-old man with atrial fibrillation developed an eruption similar to our patient on the thigh and forearm after 2 weeks of taking oral dabigatran 150 mg twice daily. It resolved without complication after topical corticosteroid use and discontinuation of dabigatran.³ In another report, a 78-year-old man presented to the emergency department after taking two 150-mg doses of dabigatran with a diffuse, full-body, pruritic rash that resolved with oral diphenhydramine and discontinuation of dabigatran.⁴ A third case described a 59-year-old man who was taking 150 mg dabigatran twice daily for 5 days before developing a rash.⁵ The fourth case involved a 74-year-old woman who developed leukocytoclastic vasculitis 1 week after taking dabigatran 150 mg twice daily.⁶

It is important to monitor for and report hypersensitivity reactions in patients taking dabigatran. Drug exanthems may cause discomfort or even herald more serious hypersensitivity reactions. Patients experiencing these reactions may discontinue therapy without notifying a physician and consequently place themselves at risk for embolism or stroke.

To the Editor:

A 71-year-old woman with hypertension and atrial fibrillation due to thyrotoxicosis was prescribed dabigatran for stroke prevention by her cardiologist. She also was taking pantoprazole, methimazole, and amiodarone at the time of presentation, all managed by her endocrinologist. She had no known drug allergies but reported a remote history of a palmar rash after eating shellfish. She otherwise had never had any problems with her skin and had no family history of psoriasis. She had a history of smoking 50 packs per year but had quit 6 months prior to presentation. After two 150-mg doses of dabigatran, she noticed numerous mildly tender and itchy eruptions on the palmar and plantar surfaces with no associated respiratory, oropharyngeal, or constitutional symptoms. She denied any recent shellfish ingestion. On dermatologic examination, numerous discreet pustules were present on the bilateral palmar and plantar surfaces with minimal erythema of the underlying skin (Figure).

A punch biopsy was taken from a newly forming lesion on the right palm. Histopathology revealed mild hyperkeratosis, spongiosis with lymphocyte exocytosis, intraepidermal vesiculation, and a sparse upper dermal and perivascular lymphohistiocytic infiltration. No neutrophils or microabscesses were seen. Staining with periodic acid–Schiff revealed no fungi, and S-100 staining revealed numerous Langerhans cells in the epidermis. Although the skin lesions clinically appeared pustular, the results were consistent with an eczematous drug reaction. Laboratory values, including a complete blood cell count, iron studies, chemistry panels, liver function, thyroid function, and coagulation studies, were remarkable only for mild anemia. The patient declined any topical or systemic skin treatment. Dabigatran was discontinued, and the lesions began to clear immediately thereafter. Dabigatran was not reintroduced. Enoxaparin subsequently was prescribed for anticoagulation. The diagnosis of a drug reaction due to dabigatran was made, which was supported with a score of 7 on the Naranjo scale (0=doubtful; 1–4=possible; 5–8=probable; ≥9=definite) for determining probability of drug-induced adverse reactions.¹ The differential diagnosis for the skin eruption included palmoplantar pustular psoriasis, dyshidrotic eczema, and allergic contact dermatitis, but the clinical history did not support these diagnoses.

Dabigatran is a direct thrombin inhibitor used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Based on results of the RE-LY (Randomization Evaluation of Long-term Anticoagulation Therapy) trial published in 2009, dabigatran 150 mg twice daily significantly reduced the risk for stroke and systemic emboli in patients with atrial fibrillation compared to warfarin (annual risk, 1.11% vs 1.69%; relative risk, 0.66; 95% CI, 0.53-0.82; P<.001) with the advantage of not requiring frequent monitoring of the international normalized ratio.² The most common adverse effect of dabigatran in this trial was dyspepsia (11.3% vs 5.8%). Drug hypersensitivity, allergic edema, and anaphylaxis were reported in less than 0.1% of patients taking dabigatran.²

According to a PubMed search of articles indexed for MEDLINE using the search terms dabigatran cutaneous reaction and dabigatran rash, 4 case reports of cutaneous eruption due to dabigatran were identified. In one report, a 20-year-old man with atrial fibrillation developed an eruption similar to our patient on the thigh and forearm after 2 weeks of taking oral dabigatran 150 mg twice daily. It resolved without complication after topical corticosteroid use and discontinuation of dabigatran.³ In another report, a 78-year-old man presented to the emergency department after taking two 150-mg doses of dabigatran with a diffuse, full-body, pruritic rash that resolved with oral diphenhydramine and discontinuation of dabigatran.⁴ A third case described a 59-year-old man who was taking 150 mg dabigatran twice daily for 5 days before developing a rash.⁵ The fourth case involved a 74-year-old woman who developed leukocytoclastic vasculitis 1 week after taking dabigatran 150 mg twice daily.⁶

It is important to monitor for and report hypersensitivity reactions in patients taking dabigatran. Drug exanthems may cause discomfort or even herald more serious hypersensitivity reactions. Patients experiencing these reactions may discontinue therapy without notifying a physician and consequently place themselves at risk for embolism or stroke.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

Books

There are a number of classic textbooks that serve as primary resources for dermatology training^1-4; however, there also are other options if memorizing these books seems a little daunting. The “first aid” books of dermatology are the Derm In-Review binder and Jain’s⁵ Dermatology: Illustrated Study Guide and Comprehensive Board Review. Mariwalla and Leffell’s⁶Primer in Dermatologic Surgery: A Study Companion is helpful for surgical review and is available at a discounted price for members of the American Society for Dermatologic Surgery (https://www.asds.net/store/product.aspx?id=3914&terms=primer%20in%20Dermatologic%20surgery). The American Academy of Dermatology (AAD) provides a list of additional textbooks that dermatology residents may find useful for board review.⁷

Guided Study

The AAD offers board review courses for dermatology residents (cost varies).⁷ The Florida Dermatology and Dermatopathology Board Review Course (http://dermatology.med.ufl.edu/education/florida-dermatology-and-dermatopathology-board-review-course/) is an annual review course held in Tampa (early registration fee, $800 [does not include travel costs]). The Oakstone Institute also offers its Dermatology Board Review Course, which is a self-study program that can be completed online for approximately $1195 (http://www.oakstone.com/dermatology-board-review-course). Be sure to take advantage of free didactics lectures, society meetings with board review courses, and study groups, as these resources can be just as helpful and more budget friendly.

Digital Resources

The Derm In-Review question bank (http://dermatologyinreview.com/Merz) is probably one of the most popular board review resources and is free to US dermatology residents; however, be cautious when using this resource, as a fair number of the answers to questions may actually be outdated or based on older studies. A group study session can help tease out why certain answers are erroneous and provide a forum for discussing what would be a more correct answer. Take advantage of the opportunity to provide feedback on this website, as your comments will improve this resource for future dermatology residents.

Beyond traditional dermatopathology textbooks, there also are some excellent mobile applications (apps) available. The Clearpath app is a user-friendly dermatopathology study tool that is free for download in the iTunes store (https://itunes.apple.com/us/app/clearpath/id540260769?mt=8). However, the app is only compatible with iPads. The Clearpath website also offers virtual study slide sets that are easier to access (http://dermpathlab.com/slide-study-set-program). Your institution’s glass slide sets also are useful for building pattern recognition skills and practicing for the actual board examination. The DermOID website (http://www.derm-oid.com), which is powered by the David Geffen School of Medicine at the University of California, Los Angeles, is another online dermatopathology study database with free registration for access to the site. Another fun way to test your dermatopathology skills is in the exhibition hall at the AAD annual meeting where some vendors may offer daily dermatopathology quizzes and prizes for the residents with the most correct answers. Also, it is worth reviewing the Cutis^® Fast Facts for Board Review (http://www.cutis.com/articles/fast-facts-for-board-review/), as this section offers many outstanding fact sheets that are an easy read and an efficient way to gain board knowledge. Some recent topics include fillers, paraneoplastic skin conditions, and medications in dermatology.

Many residents enjoy using the Anki flashcard app (http://ankisrs.net) for reviewing kodachromes. The AAD website also includes a Boards’ Fodder archive that is worth reviewing (https://www.aad.org/members/residents-fellows/boards-study-tools/boards-fodder/boards-fodder). New board review resources are constantly being posted on the AAD website, so definitely check this out. You may be able to access this resource through your residency program; it is also available for purchase ($425 for AAD members; $850 for nonmembers).

Journals

All the major dermatology journals are helpful in preparing for the board examination. Your resident journal club will likely review many of the most clinically relevant dermatology articles published over the course of your residency. Some other helpful journal resources that are recommended for board review include the Journal of the American Medical Association’s Clinical Challenge, which has many dermatologic cases (http://jama.jamanetwork.com/public/QuizzesAndPolls.aspx), and the New England Journal of Medicine’s Journal Watch (http://www.jwatch.org) and Image Challenge (http://www.nejm.org/image-challenge).

Practice Examinations

The American Board of Dermatology’s In-Training Examination is the most well-known practice examination among dermatology residents.⁸ A link to an additional practice examination usually is provided a few weeks prior to the examination. The Derm In-Review website also offers diagnostic practice examinations with some ability to custom select questions for your studying needs.

Conclusion

There are many board review resources out there. Find the ones that work for you, and be encouraged that your studying and hard work will pay off!

Books

There are a number of classic textbooks that serve as primary resources for dermatology training^1-4; however, there also are other options if memorizing these books seems a little daunting. The “first aid” books of dermatology are the Derm In-Review binder and Jain’s⁵ Dermatology: Illustrated Study Guide and Comprehensive Board Review. Mariwalla and Leffell’s⁶Primer in Dermatologic Surgery: A Study Companion is helpful for surgical review and is available at a discounted price for members of the American Society for Dermatologic Surgery (https://www.asds.net/store/product.aspx?id=3914&terms=primer%20in%20Dermatologic%20surgery). The American Academy of Dermatology (AAD) provides a list of additional textbooks that dermatology residents may find useful for board review.⁷

Guided Study

The AAD offers board review courses for dermatology residents (cost varies).⁷ The Florida Dermatology and Dermatopathology Board Review Course (http://dermatology.med.ufl.edu/education/florida-dermatology-and-dermatopathology-board-review-course/) is an annual review course held in Tampa (early registration fee, $800 [does not include travel costs]). The Oakstone Institute also offers its Dermatology Board Review Course, which is a self-study program that can be completed online for approximately $1195 (http://www.oakstone.com/dermatology-board-review-course). Be sure to take advantage of free didactics lectures, society meetings with board review courses, and study groups, as these resources can be just as helpful and more budget friendly.

Digital Resources

The Derm In-Review question bank (http://dermatologyinreview.com/Merz) is probably one of the most popular board review resources and is free to US dermatology residents; however, be cautious when using this resource, as a fair number of the answers to questions may actually be outdated or based on older studies. A group study session can help tease out why certain answers are erroneous and provide a forum for discussing what would be a more correct answer. Take advantage of the opportunity to provide feedback on this website, as your comments will improve this resource for future dermatology residents.

Beyond traditional dermatopathology textbooks, there also are some excellent mobile applications (apps) available. The Clearpath app is a user-friendly dermatopathology study tool that is free for download in the iTunes store (https://itunes.apple.com/us/app/clearpath/id540260769?mt=8). However, the app is only compatible with iPads. The Clearpath website also offers virtual study slide sets that are easier to access (http://dermpathlab.com/slide-study-set-program). Your institution’s glass slide sets also are useful for building pattern recognition skills and practicing for the actual board examination. The DermOID website (http://www.derm-oid.com), which is powered by the David Geffen School of Medicine at the University of California, Los Angeles, is another online dermatopathology study database with free registration for access to the site. Another fun way to test your dermatopathology skills is in the exhibition hall at the AAD annual meeting where some vendors may offer daily dermatopathology quizzes and prizes for the residents with the most correct answers. Also, it is worth reviewing the Cutis^® Fast Facts for Board Review (http://www.cutis.com/articles/fast-facts-for-board-review/), as this section offers many outstanding fact sheets that are an easy read and an efficient way to gain board knowledge. Some recent topics include fillers, paraneoplastic skin conditions, and medications in dermatology.

Many residents enjoy using the Anki flashcard app (http://ankisrs.net) for reviewing kodachromes. The AAD website also includes a Boards’ Fodder archive that is worth reviewing (https://www.aad.org/members/residents-fellows/boards-study-tools/boards-fodder/boards-fodder). New board review resources are constantly being posted on the AAD website, so definitely check this out. You may be able to access this resource through your residency program; it is also available for purchase ($425 for AAD members; $850 for nonmembers).

Journals

All the major dermatology journals are helpful in preparing for the board examination. Your resident journal club will likely review many of the most clinically relevant dermatology articles published over the course of your residency. Some other helpful journal resources that are recommended for board review include the Journal of the American Medical Association’s Clinical Challenge, which has many dermatologic cases (http://jama.jamanetwork.com/public/QuizzesAndPolls.aspx), and the New England Journal of Medicine’s Journal Watch (http://www.jwatch.org) and Image Challenge (http://www.nejm.org/image-challenge).

Practice Examinations

The American Board of Dermatology’s In-Training Examination is the most well-known practice examination among dermatology residents.⁸ A link to an additional practice examination usually is provided a few weeks prior to the examination. The Derm In-Review website also offers diagnostic practice examinations with some ability to custom select questions for your studying needs.

Conclusion

There are many board review resources out there. Find the ones that work for you, and be encouraged that your studying and hard work will pay off!

Books

There are a number of classic textbooks that serve as primary resources for dermatology training^1-4; however, there also are other options if memorizing these books seems a little daunting. The “first aid” books of dermatology are the Derm In-Review binder and Jain’s⁵ Dermatology: Illustrated Study Guide and Comprehensive Board Review. Mariwalla and Leffell’s⁶Primer in Dermatologic Surgery: A Study Companion is helpful for surgical review and is available at a discounted price for members of the American Society for Dermatologic Surgery (https://www.asds.net/store/product.aspx?id=3914&terms=primer%20in%20Dermatologic%20surgery). The American Academy of Dermatology (AAD) provides a list of additional textbooks that dermatology residents may find useful for board review.⁷

Guided Study

The AAD offers board review courses for dermatology residents (cost varies).⁷ The Florida Dermatology and Dermatopathology Board Review Course (http://dermatology.med.ufl.edu/education/florida-dermatology-and-dermatopathology-board-review-course/) is an annual review course held in Tampa (early registration fee, $800 [does not include travel costs]). The Oakstone Institute also offers its Dermatology Board Review Course, which is a self-study program that can be completed online for approximately $1195 (http://www.oakstone.com/dermatology-board-review-course). Be sure to take advantage of free didactics lectures, society meetings with board review courses, and study groups, as these resources can be just as helpful and more budget friendly.

Digital Resources

The Derm In-Review question bank (http://dermatologyinreview.com/Merz) is probably one of the most popular board review resources and is free to US dermatology residents; however, be cautious when using this resource, as a fair number of the answers to questions may actually be outdated or based on older studies. A group study session can help tease out why certain answers are erroneous and provide a forum for discussing what would be a more correct answer. Take advantage of the opportunity to provide feedback on this website, as your comments will improve this resource for future dermatology residents.

Beyond traditional dermatopathology textbooks, there also are some excellent mobile applications (apps) available. The Clearpath app is a user-friendly dermatopathology study tool that is free for download in the iTunes store (https://itunes.apple.com/us/app/clearpath/id540260769?mt=8). However, the app is only compatible with iPads. The Clearpath website also offers virtual study slide sets that are easier to access (http://dermpathlab.com/slide-study-set-program). Your institution’s glass slide sets also are useful for building pattern recognition skills and practicing for the actual board examination. The DermOID website (http://www.derm-oid.com), which is powered by the David Geffen School of Medicine at the University of California, Los Angeles, is another online dermatopathology study database with free registration for access to the site. Another fun way to test your dermatopathology skills is in the exhibition hall at the AAD annual meeting where some vendors may offer daily dermatopathology quizzes and prizes for the residents with the most correct answers. Also, it is worth reviewing the Cutis^® Fast Facts for Board Review (http://www.cutis.com/articles/fast-facts-for-board-review/), as this section offers many outstanding fact sheets that are an easy read and an efficient way to gain board knowledge. Some recent topics include fillers, paraneoplastic skin conditions, and medications in dermatology.

Many residents enjoy using the Anki flashcard app (http://ankisrs.net) for reviewing kodachromes. The AAD website also includes a Boards’ Fodder archive that is worth reviewing (https://www.aad.org/members/residents-fellows/boards-study-tools/boards-fodder/boards-fodder). New board review resources are constantly being posted on the AAD website, so definitely check this out. You may be able to access this resource through your residency program; it is also available for purchase ($425 for AAD members; $850 for nonmembers).

Journals

All the major dermatology journals are helpful in preparing for the board examination. Your resident journal club will likely review many of the most clinically relevant dermatology articles published over the course of your residency. Some other helpful journal resources that are recommended for board review include the Journal of the American Medical Association’s Clinical Challenge, which has many dermatologic cases (http://jama.jamanetwork.com/public/QuizzesAndPolls.aspx), and the New England Journal of Medicine’s Journal Watch (http://www.jwatch.org) and Image Challenge (http://www.nejm.org/image-challenge).

Practice Examinations

The American Board of Dermatology’s In-Training Examination is the most well-known practice examination among dermatology residents.⁸ A link to an additional practice examination usually is provided a few weeks prior to the examination. The Derm In-Review website also offers diagnostic practice examinations with some ability to custom select questions for your studying needs.

Conclusion

There are many board review resources out there. Find the ones that work for you, and be encouraged that your studying and hard work will pay off!

Merkel cells originally were described by German histopathologist Friedrich Sigmund Merkel in 1875. These unique tactile cells were described as epidermal, nondendritic, and nonkeratinizing. Merkel cells are thought to arise from the neural crest and are believed to be primary neural cells found within the basal layer of the epidermis.^1,2 They likely function primarily as slowly adapting type I mechanoreceptors. Origin from the neural crest is controversial, as other investigators have suggested derivation from epidermal keratinocytes.^1,2 Tumor cells have been linked to the amine precursor uptake and decarboxylation system.³ In 1972, Toker⁴ described several cases of trabecular or sweat gland carcinomas of the skin. Upon further investigation, the cells that comprised these tumors were found to have dense core granules on electron microscopy, typical of Merkel cells.^1,2 Other terms such as neuroendocrine carcinoma of the skin, small cell carcinoma of the skin, and anaplastic carcinoma of the skin have been used to describe Merkel cell carcinoma (MCC),¹ which was suggested by De Wolf-Peeters et al⁵ in 1980.

Despite being a rare malignancy, MCC follows an aggressive clinical course. Upon presentation, approximately 66% of patients have local disease, 27% have nodal involvement, and 7% have distant metastasis.¹ Future treatments will likely center around the novel Merkel cell polyomavirus (MCPyV) and modification of immune responses toward tumor cells. Standardization continues to be lacking in both staging and treatment of this aggressive tumor.

Epidemiology of MCC

Figure 1. A 2.3×1.5×1.2-cm, hemorrhagic, crusted, exophytic tumor on the left cheek.

Figure 2. Merkel cells are small- to medium-sized cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen (A)(H&E, original magnification ×40). Merkel cell carcinoma with trabecular pattern (B) (H&E, original magnification ×10).

Between 1986 and 2006, the incidence of MCC grew substantially.^1,2 Figures have been reported at 0.15 cases per 100,000 individuals to 0.6 cases per 100,000 individuals worldwide. In the United States, the age-adjusted incidence of MCC is estimated at 0.24 per 100,000 person-years, which is higher than the estimated 0.13 per 100,000 person-years found in Europe.³ The highest incidence worldwide has been noted in Western Australia, likely due to high levels of UV exposure.¹ The incidence of MCC in psoriasis patients who are treated with oral methoxsalen (psoralen) and UVA photochemotherapy is 100 times greater than in the general population, further supporting the role of UV light in the development of MCC.¹ White individuals have the highest incidence of MCC worldwide, with men being affected more frequently than women.^1,3 The majority of patients with MCC are diagnosed at 70 years or older.¹ Approximately 5% of reported MCC patients are diagnosed before 50 years of age.² Immunosuppression and immunodeficiency likely play a role in the pathogenesis of MCC, and the incidence is increased in solid organ transplant recipients, most commonly renal transplant recipients,¹ as well as individuals with chronic lymphocytic leukemia, human immunodeficiency virus infection, and AIDS.^1,3 Patients with autoimmune diseases such as rheumatoid arthritis also are at increased risk for MCC.³ Individuals who are diagnosed with MCC are at an increased risk for development of other malignancies including nonmelanoma skin cancers, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.³

Clinical Presentation of MCC

The clinical presentation of MCC can be variable. Most tumors present as firm, red to purple, nontender papules or nodules (Figure 1).¹ Tumor size may range from 2 to 200 mm but is most commonly less than 20 mm.² Growth can be rapid, and tumors are most commonly located on sun-exposed skin. The head and neck areas account for 48% of all MCC cases,¹ with the eyelids being frequently involved.² Merkel cell carcinoma also has been reported on the arms, legs, trunk, back, and buttocks.¹ Non–sun-exposed areas are less commonly affected. Mucosal sites (eg, larynx, nasal cavity, pharynx, mouth) account for 5% of primary MCCs.¹ Merkel cell carcinoma also has been reported to affect the vulva and penis. Subcutaneous primary MCC has presented without overlying epidermal changes.¹ In a case series by Heath et al,⁶ 14% (27/195) of MCC patients presented with nodal disease without any identifiable primary tumor, with the inguinal nodal chain being the most common for this presentation. It currently is not known whether these nodal tumors are primary tumors or metastatic disease with a regression of the primary tumor.¹

Histopathology of MCC

Figure 3. Positive chromogranin staining (A)(original magnification ×40). Cytokeratin 20 staining in the characteristic paranuclear dot–like pattern (B)(original magnification ×40). Negative thyroid transcription factor 1 staining (C)(original magnification ×40).

Merkel cells are small- to medium-sized basophilic cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen on histopathology (Figure 2A).¹ Some tumor cells have more vesicular chromatin, multiple small nucleoli, irregular contours, and more abundant cytoplasm. In some reports, irregular contours and abundant cytoplasm were associated with no detectible MCPyV infection.^1,3 Merkel cell carcinomas have a primarily nodular architecture, and classification is based on growth pattern and cell size. Three histopathologic growth patterns have been described: nodular, infiltrative, and trabecular. The trabecular pattern is composed of interconnecting strands ofcells (Figure 2B). Tumors with solely intraepidermal involvement (MCC in situ) have been described but are exceedingly rare.¹ Cell types are classified according to size, with the intermediate cell type being the most common. The small cell variant may be mistaken for a lymphocytic infiltrate due to the similar size and appearance of both types of cells.^1,3

Merkel cell carcinomas can have histopathological overlap with lymphomas, small cell lung cancers, carcinoid tumors, primitive neuroectodermal tumors, neuroblastomas, small cell osteosarcomas, rhabdomyosarcomas, or Ewing sarcomas.^1,3 Specifically, differentiation from small cell carcinoma of the lung is of utmost importance. Merkel cell carcinoma stains positively for cytokeratins 8, 18, 19, and 20. The neuroendocrine markers chromogranin (Figure 3A), synaptophysin, and neuron-specific enolase also may show positive staining. Cytokeratin 20, low-molecular-weight cytokeratins (CAM 5.2), and neurofilament immunostains have a high sensitivity for MCC and are the most frequently used.¹ Cytokeratin 20 stains in the characteristic paranuclear dot–like pattern, which is a hallmark of MCC (Figure 3B). Cytokeratin 20 positivity in conjunction with negative staining for thyroid transcription factor 1 (Figure 3C) and cytokeratin 7 can aid in differentiation from small cell carcinoma of the lung.^1,3

Pathogenesis of MCC

In 2008, Feng et al⁷ discovered a novel polyomavirus associated with the development of MCC. This novel polyomavirus, MCPyV, is found in approximately 80% of all cases of MCC. Seventeen members of the polyomavirus family have been identified, 9 of which have been found to infect humans, including BK virus, JC virus, WU, MCPyV, human polyomavirus 6, human polyomavirus 7, trichodysplasia spinulosa–associated polyomavirus, human polyomavirus 9, and Simian virus 40.¹ Merkel cell polyomavirus infection is found in approximately 60% of the general population and exposure likely occurs early in life. The virus likely is transmitted through skin shedding and nasal secretions, though it also has been found in urine specimens.³ Currently, there is no evidence to suggest vertical viral transmission from mother to fetus.

Merkel cell polyomavirus is composed of early and late gene regions. The early gene region contains both large T antigen (LT) and small T antigen reading frames, which are necessary for viral replication.⁸ The late region is responsible for encoding viral proteins necessary for viral capsid assembly. Mutations found in viral protein 1 prevent formation of viral particles.⁹ Large T antigen is substantially overexpressed in MCC and is responsible for tumor suppression through retinoblastoma tumor suppressor protein. It also serves as a binding domain for both heat shock proteins and helicases.^8,10 These domains allow the polyomaviruses to use host-cell machinery for viral genome replication while targeting tumor suppressor proteins.⁸ Upon viral integration into host DNA, viral replication ceases while oncogenic function persists.

The exact mechanism by which the MCPyV contributes to the development of MCC still has yet to be identified. Hypotheses suggest a combination of viral infection with external mutagens (eg, UV radiation). Experimental observations suggest viral contribution is likely due to the large percentage of MCCs that are positive for MCPyV, the identification of LT antigen expression and the role it plays in preserving cell cycle progression, and the role persistent LT antigen expression plays in continued growth of MCC cell lines in vitro.⁸ Two important cell line preservation mechanisms ensure continued tumor growth, including prevention of apoptosis triggered by DNA damage response mechanisms following UV damage and interaction with the retinoblastoma tumor suppressor protein allowing continued growth.^8,11 Other important factors in tumor growth and survival may be the inhibition of apoptosis through the BCL2 (B-cell chronic lymphocytic leukemia/lymphoma 2) proto-oncogene and survivin (baculoviral inhibitor of apoptosis repeat-containing 5 [BIRC5]).¹² Survivin has been found to play an important role in MCPyV-positive MCCs.^12,13 It has been suggested that lymphangiogenesis in MCC likely is driven by vascular endothelial growth factor-C⁺CD68⁺CD163⁺ M2 macrophages.¹⁴ Another survival mechanism specific to polyomaviruses is their ability to interfere with the p53 tumor suppressor pathway.⁸ Loss of p53 expression by tumor cell nuclei has been associated with poor prognosis.¹⁵

Immune Response

Immune response as a role in tumor progression can be primarily centered on the concept of persistent antigen expression as a means of immune downregulation. Dunn et al¹⁶ suggested that cancer cells must interact through 3 consecutive phases with the host immune system (immunoediting hypothesis). In the elimination phase, the host immune system is able to recognize and destroy newly transformed cells through both the innate and adaptive immune systems. The second equilibrium phase allows the tumor to remain dormant and growth remains stagnant. Lastly, the tumor is allowed to evade the immune system through the escape phase.⁸

Host immune responses play an important role in both the progression and prognosis of MCC. High anti-MCPyV capsid antibody titers have been associated with better progression-free survival in some patients.⁸ Patients with high antibody titers (>10,000) likely have better progression-free survival than those with low antibody titers (<10,000).¹⁷ Antibody titers to the LT antigen may serve as a biomarker of MCC disease burden in the future. Rising LT antigen titers have been shown to correlate with disease progression and falling titers correlate with successful treatment.⁸ Tumoral infiltration of CD8⁺ T lymphocytes has been shown to be a predictor of survival compared to no intratumoral infiltration.⁶ Sihto et al¹⁸ suggested that this better prognosis from high intratumoral infiltration is not specific to MCPyV-positive MCC; however, it does highlight an important aspect of tumor evasion through the downregulation of cell surface expression of class I major histocompatibility complex antigens, which allows presentation of tumor intracellular peptides to CD8⁺ T lymphocytes.⁸ Upregulation of this specific immune response may play a role in the future treatment of MCC.

Staging and Prognosis

Due to the extremely aggressive nature of MCC, patients with local disease and tumors 2 cm or smaller in diameter have a 66% survival at 5 years.^1,3 The 5-year survival rate for patients with local metastasis to regional lymph nodes ranges from 26% to 42%. Patients with distant metastasis have an 18% survival rate at 5 years.^1,3 Data suggest that sentinel lymph node biopsy should be performed on all patients with MCC regardless of tumor size.¹ There are no consensus guidelines to date regarding imaging for the staging of MCC patients. It is suggested that (18F)fluorodeoxyglucose positron emission tomography alone or in combination with computed tomography (CT) may be of value as a single whole-body diagnostic tool for accurate staging.¹⁰ It also has been suggested that (18F)fluorodeoxyglucose positron emission tomography and CT may offer more accurate staging than other screening modalities such as CT alone or magnetic resonance imaging.^14,19

Treatment of MCC

Surgery remains the mainstay of treatment of MCC. Current National Comprehensive Cancer Network guidelines²⁰ recommend 1- to 2-cm margins for wide local excision or treatment with Mohs micrographic surgery. Sentinel lymph node biopsy should be performed intraoperatively in patients undergoing wide local excision and preoperatively for patients undergoing Mohs micrographic surgery due to potential alterations in lymphatic drainage that may affect lymphoscintigraphy.¹

Radiation may be used as primary or adjuvant therapy in patients with MCC. Radiation as primary therapy generally is reserved for patients who are not surgical candidates. It has been suggested that there was no difference in outcome in a small group of patients treated with radiation alone compared to patients who underwent surgery and radiation to the tumor bed.¹ Current guidelines suggest a small group of patients may not require adjuvant therapy following adequate resection of some small tumors, and clinical observation may be appropriate.^1,3 Chemotherapy may play a palliative role in patients with metastatic MCC. Merkel cell carcinoma has been shown to be chemosensitive but with a high recurrence rate.¹ Because the immune system plays an important role in disease prognosis, having an intact immune system likely is paramount in the prevention of further disease progression.

Future Treatments of MCC

Future treatment of MCC may be focused on the viral etiology of most tumors and upregulation of the immune response, which may lead to the possibility of specifically interfering with virus-specific oncoproteins and stimulation of immune responses to virally infected tumor cells.⁸ The MCPyV large T antigen has been found to be overexpressed in some tumors and may serve as a specific target of therapy.^10,21 Survivin, a key cell cycle protein encoded by LT antigen, may be an interesting target given its implication in other cancers.¹³ Other potential nonviral molecular target antigens include the oncoprotein H1P1 that interacts with c-KIT.⁸ Specific immunostimulatory cytokines that may be used to upregulate the immune response to tumoral cells may include IL-2, IL-12, IL-15, or IL-21. Therapeutic agents that may be studied in the future to target the immune exhaustion phenomenon associated with tumorigenesis include ipilimumab (cytotoxic T lymphocyte antigen 4 receptor-blocking agent) as well as programmed cell death 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1).⁸ Neuroendocrine tumors including MCC tend to be highly vascular and express vascular endothelial growth factors and platelet-derived growth factors, which may be other potential therapeutic targets. It has been reported that approximately 95% of MCC patients have CD56⁺ tumors, and current clinical trials suggest a promising therapeutic response with the immunogen anti-CD56 monoclonal antibody.³

Conclusion

Merkel cell carcinoma is a rare aggressive neuroendocrine tumor that has been associated with a novel polyomavirus. Merkel cell carcinoma tends to affect elderly and immunocompromised patients as well as white individuals. Tumors are most often found in areas of high UV exposure and clinically on sun-exposed skin. Merkel cell polyomavirus is associated with approximately 80% of tumors, and tumorigenesis likely is caused by a number of sequential steps from viral integration into host DNA, mutagenic events, and specific immune responses. Currently there are no consensus guidelines for using imaging for staging of MCCs, but sentinel lymph node biopsy is recommended for all cases due to the aggressive nature of even smaller tumors. Surgery remains the mainstay of treatment, and radiation therapy may be used as a primary or adjuvant treatment. Chemotherapy usually is reserved for patients with metastatic disease purely for palliation. Future treatments of MCC likely will center on the viral etiology of MCC and upregulation of immune responses to virally infected tumor cells.

Merkel cells originally were described by German histopathologist Friedrich Sigmund Merkel in 1875. These unique tactile cells were described as epidermal, nondendritic, and nonkeratinizing. Merkel cells are thought to arise from the neural crest and are believed to be primary neural cells found within the basal layer of the epidermis.^1,2 They likely function primarily as slowly adapting type I mechanoreceptors. Origin from the neural crest is controversial, as other investigators have suggested derivation from epidermal keratinocytes.^1,2 Tumor cells have been linked to the amine precursor uptake and decarboxylation system.³ In 1972, Toker⁴ described several cases of trabecular or sweat gland carcinomas of the skin. Upon further investigation, the cells that comprised these tumors were found to have dense core granules on electron microscopy, typical of Merkel cells.^1,2 Other terms such as neuroendocrine carcinoma of the skin, small cell carcinoma of the skin, and anaplastic carcinoma of the skin have been used to describe Merkel cell carcinoma (MCC),¹ which was suggested by De Wolf-Peeters et al⁵ in 1980.

Despite being a rare malignancy, MCC follows an aggressive clinical course. Upon presentation, approximately 66% of patients have local disease, 27% have nodal involvement, and 7% have distant metastasis.¹ Future treatments will likely center around the novel Merkel cell polyomavirus (MCPyV) and modification of immune responses toward tumor cells. Standardization continues to be lacking in both staging and treatment of this aggressive tumor.

Epidemiology of MCC

Figure 1. A 2.3×1.5×1.2-cm, hemorrhagic, crusted, exophytic tumor on the left cheek.

Figure 2. Merkel cells are small- to medium-sized cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen (A)(H&E, original magnification ×40). Merkel cell carcinoma with trabecular pattern (B) (H&E, original magnification ×10).

Between 1986 and 2006, the incidence of MCC grew substantially.^1,2 Figures have been reported at 0.15 cases per 100,000 individuals to 0.6 cases per 100,000 individuals worldwide. In the United States, the age-adjusted incidence of MCC is estimated at 0.24 per 100,000 person-years, which is higher than the estimated 0.13 per 100,000 person-years found in Europe.³ The highest incidence worldwide has been noted in Western Australia, likely due to high levels of UV exposure.¹ The incidence of MCC in psoriasis patients who are treated with oral methoxsalen (psoralen) and UVA photochemotherapy is 100 times greater than in the general population, further supporting the role of UV light in the development of MCC.¹ White individuals have the highest incidence of MCC worldwide, with men being affected more frequently than women.^1,3 The majority of patients with MCC are diagnosed at 70 years or older.¹ Approximately 5% of reported MCC patients are diagnosed before 50 years of age.² Immunosuppression and immunodeficiency likely play a role in the pathogenesis of MCC, and the incidence is increased in solid organ transplant recipients, most commonly renal transplant recipients,¹ as well as individuals with chronic lymphocytic leukemia, human immunodeficiency virus infection, and AIDS.^1,3 Patients with autoimmune diseases such as rheumatoid arthritis also are at increased risk for MCC.³ Individuals who are diagnosed with MCC are at an increased risk for development of other malignancies including nonmelanoma skin cancers, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.³

Clinical Presentation of MCC

The clinical presentation of MCC can be variable. Most tumors present as firm, red to purple, nontender papules or nodules (Figure 1).¹ Tumor size may range from 2 to 200 mm but is most commonly less than 20 mm.² Growth can be rapid, and tumors are most commonly located on sun-exposed skin. The head and neck areas account for 48% of all MCC cases,¹ with the eyelids being frequently involved.² Merkel cell carcinoma also has been reported on the arms, legs, trunk, back, and buttocks.¹ Non–sun-exposed areas are less commonly affected. Mucosal sites (eg, larynx, nasal cavity, pharynx, mouth) account for 5% of primary MCCs.¹ Merkel cell carcinoma also has been reported to affect the vulva and penis. Subcutaneous primary MCC has presented without overlying epidermal changes.¹ In a case series by Heath et al,⁶ 14% (27/195) of MCC patients presented with nodal disease without any identifiable primary tumor, with the inguinal nodal chain being the most common for this presentation. It currently is not known whether these nodal tumors are primary tumors or metastatic disease with a regression of the primary tumor.¹

Histopathology of MCC

Figure 3. Positive chromogranin staining (A)(original magnification ×40). Cytokeratin 20 staining in the characteristic paranuclear dot–like pattern (B)(original magnification ×40). Negative thyroid transcription factor 1 staining (C)(original magnification ×40).

Merkel cells are small- to medium-sized basophilic cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen on histopathology (Figure 2A).¹ Some tumor cells have more vesicular chromatin, multiple small nucleoli, irregular contours, and more abundant cytoplasm. In some reports, irregular contours and abundant cytoplasm were associated with no detectible MCPyV infection.^1,3 Merkel cell carcinomas have a primarily nodular architecture, and classification is based on growth pattern and cell size. Three histopathologic growth patterns have been described: nodular, infiltrative, and trabecular. The trabecular pattern is composed of interconnecting strands ofcells (Figure 2B). Tumors with solely intraepidermal involvement (MCC in situ) have been described but are exceedingly rare.¹ Cell types are classified according to size, with the intermediate cell type being the most common. The small cell variant may be mistaken for a lymphocytic infiltrate due to the similar size and appearance of both types of cells.^1,3

Merkel cell carcinomas can have histopathological overlap with lymphomas, small cell lung cancers, carcinoid tumors, primitive neuroectodermal tumors, neuroblastomas, small cell osteosarcomas, rhabdomyosarcomas, or Ewing sarcomas.^1,3 Specifically, differentiation from small cell carcinoma of the lung is of utmost importance. Merkel cell carcinoma stains positively for cytokeratins 8, 18, 19, and 20. The neuroendocrine markers chromogranin (Figure 3A), synaptophysin, and neuron-specific enolase also may show positive staining. Cytokeratin 20, low-molecular-weight cytokeratins (CAM 5.2), and neurofilament immunostains have a high sensitivity for MCC and are the most frequently used.¹ Cytokeratin 20 stains in the characteristic paranuclear dot–like pattern, which is a hallmark of MCC (Figure 3B). Cytokeratin 20 positivity in conjunction with negative staining for thyroid transcription factor 1 (Figure 3C) and cytokeratin 7 can aid in differentiation from small cell carcinoma of the lung.^1,3

Pathogenesis of MCC

In 2008, Feng et al⁷ discovered a novel polyomavirus associated with the development of MCC. This novel polyomavirus, MCPyV, is found in approximately 80% of all cases of MCC. Seventeen members of the polyomavirus family have been identified, 9 of which have been found to infect humans, including BK virus, JC virus, WU, MCPyV, human polyomavirus 6, human polyomavirus 7, trichodysplasia spinulosa–associated polyomavirus, human polyomavirus 9, and Simian virus 40.¹ Merkel cell polyomavirus infection is found in approximately 60% of the general population and exposure likely occurs early in life. The virus likely is transmitted through skin shedding and nasal secretions, though it also has been found in urine specimens.³ Currently, there is no evidence to suggest vertical viral transmission from mother to fetus.

Merkel cell polyomavirus is composed of early and late gene regions. The early gene region contains both large T antigen (LT) and small T antigen reading frames, which are necessary for viral replication.⁸ The late region is responsible for encoding viral proteins necessary for viral capsid assembly. Mutations found in viral protein 1 prevent formation of viral particles.⁹ Large T antigen is substantially overexpressed in MCC and is responsible for tumor suppression through retinoblastoma tumor suppressor protein. It also serves as a binding domain for both heat shock proteins and helicases.^8,10 These domains allow the polyomaviruses to use host-cell machinery for viral genome replication while targeting tumor suppressor proteins.⁸ Upon viral integration into host DNA, viral replication ceases while oncogenic function persists.

The exact mechanism by which the MCPyV contributes to the development of MCC still has yet to be identified. Hypotheses suggest a combination of viral infection with external mutagens (eg, UV radiation). Experimental observations suggest viral contribution is likely due to the large percentage of MCCs that are positive for MCPyV, the identification of LT antigen expression and the role it plays in preserving cell cycle progression, and the role persistent LT antigen expression plays in continued growth of MCC cell lines in vitro.⁸ Two important cell line preservation mechanisms ensure continued tumor growth, including prevention of apoptosis triggered by DNA damage response mechanisms following UV damage and interaction with the retinoblastoma tumor suppressor protein allowing continued growth.^8,11 Other important factors in tumor growth and survival may be the inhibition of apoptosis through the BCL2 (B-cell chronic lymphocytic leukemia/lymphoma 2) proto-oncogene and survivin (baculoviral inhibitor of apoptosis repeat-containing 5 [BIRC5]).¹² Survivin has been found to play an important role in MCPyV-positive MCCs.^12,13 It has been suggested that lymphangiogenesis in MCC likely is driven by vascular endothelial growth factor-C⁺CD68⁺CD163⁺ M2 macrophages.¹⁴ Another survival mechanism specific to polyomaviruses is their ability to interfere with the p53 tumor suppressor pathway.⁸ Loss of p53 expression by tumor cell nuclei has been associated with poor prognosis.¹⁵

Immune Response

Immune response as a role in tumor progression can be primarily centered on the concept of persistent antigen expression as a means of immune downregulation. Dunn et al¹⁶ suggested that cancer cells must interact through 3 consecutive phases with the host immune system (immunoediting hypothesis). In the elimination phase, the host immune system is able to recognize and destroy newly transformed cells through both the innate and adaptive immune systems. The second equilibrium phase allows the tumor to remain dormant and growth remains stagnant. Lastly, the tumor is allowed to evade the immune system through the escape phase.⁸

Host immune responses play an important role in both the progression and prognosis of MCC. High anti-MCPyV capsid antibody titers have been associated with better progression-free survival in some patients.⁸ Patients with high antibody titers (>10,000) likely have better progression-free survival than those with low antibody titers (<10,000).¹⁷ Antibody titers to the LT antigen may serve as a biomarker of MCC disease burden in the future. Rising LT antigen titers have been shown to correlate with disease progression and falling titers correlate with successful treatment.⁸ Tumoral infiltration of CD8⁺ T lymphocytes has been shown to be a predictor of survival compared to no intratumoral infiltration.⁶ Sihto et al¹⁸ suggested that this better prognosis from high intratumoral infiltration is not specific to MCPyV-positive MCC; however, it does highlight an important aspect of tumor evasion through the downregulation of cell surface expression of class I major histocompatibility complex antigens, which allows presentation of tumor intracellular peptides to CD8⁺ T lymphocytes.⁸ Upregulation of this specific immune response may play a role in the future treatment of MCC.

Staging and Prognosis

Due to the extremely aggressive nature of MCC, patients with local disease and tumors 2 cm or smaller in diameter have a 66% survival at 5 years.^1,3 The 5-year survival rate for patients with local metastasis to regional lymph nodes ranges from 26% to 42%. Patients with distant metastasis have an 18% survival rate at 5 years.^1,3 Data suggest that sentinel lymph node biopsy should be performed on all patients with MCC regardless of tumor size.¹ There are no consensus guidelines to date regarding imaging for the staging of MCC patients. It is suggested that (18F)fluorodeoxyglucose positron emission tomography alone or in combination with computed tomography (CT) may be of value as a single whole-body diagnostic tool for accurate staging.¹⁰ It also has been suggested that (18F)fluorodeoxyglucose positron emission tomography and CT may offer more accurate staging than other screening modalities such as CT alone or magnetic resonance imaging.^14,19

Treatment of MCC

Surgery remains the mainstay of treatment of MCC. Current National Comprehensive Cancer Network guidelines²⁰ recommend 1- to 2-cm margins for wide local excision or treatment with Mohs micrographic surgery. Sentinel lymph node biopsy should be performed intraoperatively in patients undergoing wide local excision and preoperatively for patients undergoing Mohs micrographic surgery due to potential alterations in lymphatic drainage that may affect lymphoscintigraphy.¹

Radiation may be used as primary or adjuvant therapy in patients with MCC. Radiation as primary therapy generally is reserved for patients who are not surgical candidates. It has been suggested that there was no difference in outcome in a small group of patients treated with radiation alone compared to patients who underwent surgery and radiation to the tumor bed.¹ Current guidelines suggest a small group of patients may not require adjuvant therapy following adequate resection of some small tumors, and clinical observation may be appropriate.^1,3 Chemotherapy may play a palliative role in patients with metastatic MCC. Merkel cell carcinoma has been shown to be chemosensitive but with a high recurrence rate.¹ Because the immune system plays an important role in disease prognosis, having an intact immune system likely is paramount in the prevention of further disease progression.

Future Treatments of MCC

Future treatment of MCC may be focused on the viral etiology of most tumors and upregulation of the immune response, which may lead to the possibility of specifically interfering with virus-specific oncoproteins and stimulation of immune responses to virally infected tumor cells.⁸ The MCPyV large T antigen has been found to be overexpressed in some tumors and may serve as a specific target of therapy.^10,21 Survivin, a key cell cycle protein encoded by LT antigen, may be an interesting target given its implication in other cancers.¹³ Other potential nonviral molecular target antigens include the oncoprotein H1P1 that interacts with c-KIT.⁸ Specific immunostimulatory cytokines that may be used to upregulate the immune response to tumoral cells may include IL-2, IL-12, IL-15, or IL-21. Therapeutic agents that may be studied in the future to target the immune exhaustion phenomenon associated with tumorigenesis include ipilimumab (cytotoxic T lymphocyte antigen 4 receptor-blocking agent) as well as programmed cell death 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1).⁸ Neuroendocrine tumors including MCC tend to be highly vascular and express vascular endothelial growth factors and platelet-derived growth factors, which may be other potential therapeutic targets. It has been reported that approximately 95% of MCC patients have CD56⁺ tumors, and current clinical trials suggest a promising therapeutic response with the immunogen anti-CD56 monoclonal antibody.³

Conclusion

Merkel cell carcinoma is a rare aggressive neuroendocrine tumor that has been associated with a novel polyomavirus. Merkel cell carcinoma tends to affect elderly and immunocompromised patients as well as white individuals. Tumors are most often found in areas of high UV exposure and clinically on sun-exposed skin. Merkel cell polyomavirus is associated with approximately 80% of tumors, and tumorigenesis likely is caused by a number of sequential steps from viral integration into host DNA, mutagenic events, and specific immune responses. Currently there are no consensus guidelines for using imaging for staging of MCCs, but sentinel lymph node biopsy is recommended for all cases due to the aggressive nature of even smaller tumors. Surgery remains the mainstay of treatment, and radiation therapy may be used as a primary or adjuvant treatment. Chemotherapy usually is reserved for patients with metastatic disease purely for palliation. Future treatments of MCC likely will center on the viral etiology of MCC and upregulation of immune responses to virally infected tumor cells.

Merkel cells originally were described by German histopathologist Friedrich Sigmund Merkel in 1875. These unique tactile cells were described as epidermal, nondendritic, and nonkeratinizing. Merkel cells are thought to arise from the neural crest and are believed to be primary neural cells found within the basal layer of the epidermis.^1,2 They likely function primarily as slowly adapting type I mechanoreceptors. Origin from the neural crest is controversial, as other investigators have suggested derivation from epidermal keratinocytes.^1,2 Tumor cells have been linked to the amine precursor uptake and decarboxylation system.³ In 1972, Toker⁴ described several cases of trabecular or sweat gland carcinomas of the skin. Upon further investigation, the cells that comprised these tumors were found to have dense core granules on electron microscopy, typical of Merkel cells.^1,2 Other terms such as neuroendocrine carcinoma of the skin, small cell carcinoma of the skin, and anaplastic carcinoma of the skin have been used to describe Merkel cell carcinoma (MCC),¹ which was suggested by De Wolf-Peeters et al⁵ in 1980.

Despite being a rare malignancy, MCC follows an aggressive clinical course. Upon presentation, approximately 66% of patients have local disease, 27% have nodal involvement, and 7% have distant metastasis.¹ Future treatments will likely center around the novel Merkel cell polyomavirus (MCPyV) and modification of immune responses toward tumor cells. Standardization continues to be lacking in both staging and treatment of this aggressive tumor.

Epidemiology of MCC

Figure 1. A 2.3×1.5×1.2-cm, hemorrhagic, crusted, exophytic tumor on the left cheek.

Figure 2. Merkel cells are small- to medium-sized cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen (A)(H&E, original magnification ×40). Merkel cell carcinoma with trabecular pattern (B) (H&E, original magnification ×10).

Between 1986 and 2006, the incidence of MCC grew substantially.^1,2 Figures have been reported at 0.15 cases per 100,000 individuals to 0.6 cases per 100,000 individuals worldwide. In the United States, the age-adjusted incidence of MCC is estimated at 0.24 per 100,000 person-years, which is higher than the estimated 0.13 per 100,000 person-years found in Europe.³ The highest incidence worldwide has been noted in Western Australia, likely due to high levels of UV exposure.¹ The incidence of MCC in psoriasis patients who are treated with oral methoxsalen (psoralen) and UVA photochemotherapy is 100 times greater than in the general population, further supporting the role of UV light in the development of MCC.¹ White individuals have the highest incidence of MCC worldwide, with men being affected more frequently than women.^1,3 The majority of patients with MCC are diagnosed at 70 years or older.¹ Approximately 5% of reported MCC patients are diagnosed before 50 years of age.² Immunosuppression and immunodeficiency likely play a role in the pathogenesis of MCC, and the incidence is increased in solid organ transplant recipients, most commonly renal transplant recipients,¹ as well as individuals with chronic lymphocytic leukemia, human immunodeficiency virus infection, and AIDS.^1,3 Patients with autoimmune diseases such as rheumatoid arthritis also are at increased risk for MCC.³ Individuals who are diagnosed with MCC are at an increased risk for development of other malignancies including nonmelanoma skin cancers, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma.³

Clinical Presentation of MCC

The clinical presentation of MCC can be variable. Most tumors present as firm, red to purple, nontender papules or nodules (Figure 1).¹ Tumor size may range from 2 to 200 mm but is most commonly less than 20 mm.² Growth can be rapid, and tumors are most commonly located on sun-exposed skin. The head and neck areas account for 48% of all MCC cases,¹ with the eyelids being frequently involved.² Merkel cell carcinoma also has been reported on the arms, legs, trunk, back, and buttocks.¹ Non–sun-exposed areas are less commonly affected. Mucosal sites (eg, larynx, nasal cavity, pharynx, mouth) account for 5% of primary MCCs.¹ Merkel cell carcinoma also has been reported to affect the vulva and penis. Subcutaneous primary MCC has presented without overlying epidermal changes.¹ In a case series by Heath et al,⁶ 14% (27/195) of MCC patients presented with nodal disease without any identifiable primary tumor, with the inguinal nodal chain being the most common for this presentation. It currently is not known whether these nodal tumors are primary tumors or metastatic disease with a regression of the primary tumor.¹

Histopathology of MCC

Figure 3. Positive chromogranin staining (A)(original magnification ×40). Cytokeratin 20 staining in the characteristic paranuclear dot–like pattern (B)(original magnification ×40). Negative thyroid transcription factor 1 staining (C)(original magnification ×40).

Merkel cells are small- to medium-sized basophilic cells with round nuclei and scant cytoplasm. Granular or stippled chromatin can be seen on histopathology (Figure 2A).¹ Some tumor cells have more vesicular chromatin, multiple small nucleoli, irregular contours, and more abundant cytoplasm. In some reports, irregular contours and abundant cytoplasm were associated with no detectible MCPyV infection.^1,3 Merkel cell carcinomas have a primarily nodular architecture, and classification is based on growth pattern and cell size. Three histopathologic growth patterns have been described: nodular, infiltrative, and trabecular. The trabecular pattern is composed of interconnecting strands ofcells (Figure 2B). Tumors with solely intraepidermal involvement (MCC in situ) have been described but are exceedingly rare.¹ Cell types are classified according to size, with the intermediate cell type being the most common. The small cell variant may be mistaken for a lymphocytic infiltrate due to the similar size and appearance of both types of cells.^1,3

Merkel cell carcinomas can have histopathological overlap with lymphomas, small cell lung cancers, carcinoid tumors, primitive neuroectodermal tumors, neuroblastomas, small cell osteosarcomas, rhabdomyosarcomas, or Ewing sarcomas.^1,3 Specifically, differentiation from small cell carcinoma of the lung is of utmost importance. Merkel cell carcinoma stains positively for cytokeratins 8, 18, 19, and 20. The neuroendocrine markers chromogranin (Figure 3A), synaptophysin, and neuron-specific enolase also may show positive staining. Cytokeratin 20, low-molecular-weight cytokeratins (CAM 5.2), and neurofilament immunostains have a high sensitivity for MCC and are the most frequently used.¹ Cytokeratin 20 stains in the characteristic paranuclear dot–like pattern, which is a hallmark of MCC (Figure 3B). Cytokeratin 20 positivity in conjunction with negative staining for thyroid transcription factor 1 (Figure 3C) and cytokeratin 7 can aid in differentiation from small cell carcinoma of the lung.^1,3

Pathogenesis of MCC

In 2008, Feng et al⁷ discovered a novel polyomavirus associated with the development of MCC. This novel polyomavirus, MCPyV, is found in approximately 80% of all cases of MCC. Seventeen members of the polyomavirus family have been identified, 9 of which have been found to infect humans, including BK virus, JC virus, WU, MCPyV, human polyomavirus 6, human polyomavirus 7, trichodysplasia spinulosa–associated polyomavirus, human polyomavirus 9, and Simian virus 40.¹ Merkel cell polyomavirus infection is found in approximately 60% of the general population and exposure likely occurs early in life. The virus likely is transmitted through skin shedding and nasal secretions, though it also has been found in urine specimens.³ Currently, there is no evidence to suggest vertical viral transmission from mother to fetus.

Merkel cell polyomavirus is composed of early and late gene regions. The early gene region contains both large T antigen (LT) and small T antigen reading frames, which are necessary for viral replication.⁸ The late region is responsible for encoding viral proteins necessary for viral capsid assembly. Mutations found in viral protein 1 prevent formation of viral particles.⁹ Large T antigen is substantially overexpressed in MCC and is responsible for tumor suppression through retinoblastoma tumor suppressor protein. It also serves as a binding domain for both heat shock proteins and helicases.^8,10 These domains allow the polyomaviruses to use host-cell machinery for viral genome replication while targeting tumor suppressor proteins.⁸ Upon viral integration into host DNA, viral replication ceases while oncogenic function persists.

The exact mechanism by which the MCPyV contributes to the development of MCC still has yet to be identified. Hypotheses suggest a combination of viral infection with external mutagens (eg, UV radiation). Experimental observations suggest viral contribution is likely due to the large percentage of MCCs that are positive for MCPyV, the identification of LT antigen expression and the role it plays in preserving cell cycle progression, and the role persistent LT antigen expression plays in continued growth of MCC cell lines in vitro.⁸ Two important cell line preservation mechanisms ensure continued tumor growth, including prevention of apoptosis triggered by DNA damage response mechanisms following UV damage and interaction with the retinoblastoma tumor suppressor protein allowing continued growth.^8,11 Other important factors in tumor growth and survival may be the inhibition of apoptosis through the BCL2 (B-cell chronic lymphocytic leukemia/lymphoma 2) proto-oncogene and survivin (baculoviral inhibitor of apoptosis repeat-containing 5 [BIRC5]).¹² Survivin has been found to play an important role in MCPyV-positive MCCs.^12,13 It has been suggested that lymphangiogenesis in MCC likely is driven by vascular endothelial growth factor-C⁺CD68⁺CD163⁺ M2 macrophages.¹⁴ Another survival mechanism specific to polyomaviruses is their ability to interfere with the p53 tumor suppressor pathway.⁸ Loss of p53 expression by tumor cell nuclei has been associated with poor prognosis.¹⁵

Immune Response

Immune response as a role in tumor progression can be primarily centered on the concept of persistent antigen expression as a means of immune downregulation. Dunn et al¹⁶ suggested that cancer cells must interact through 3 consecutive phases with the host immune system (immunoediting hypothesis). In the elimination phase, the host immune system is able to recognize and destroy newly transformed cells through both the innate and adaptive immune systems. The second equilibrium phase allows the tumor to remain dormant and growth remains stagnant. Lastly, the tumor is allowed to evade the immune system through the escape phase.⁸

Host immune responses play an important role in both the progression and prognosis of MCC. High anti-MCPyV capsid antibody titers have been associated with better progression-free survival in some patients.⁸ Patients with high antibody titers (>10,000) likely have better progression-free survival than those with low antibody titers (<10,000).¹⁷ Antibody titers to the LT antigen may serve as a biomarker of MCC disease burden in the future. Rising LT antigen titers have been shown to correlate with disease progression and falling titers correlate with successful treatment.⁸ Tumoral infiltration of CD8⁺ T lymphocytes has been shown to be a predictor of survival compared to no intratumoral infiltration.⁶ Sihto et al¹⁸ suggested that this better prognosis from high intratumoral infiltration is not specific to MCPyV-positive MCC; however, it does highlight an important aspect of tumor evasion through the downregulation of cell surface expression of class I major histocompatibility complex antigens, which allows presentation of tumor intracellular peptides to CD8⁺ T lymphocytes.⁸ Upregulation of this specific immune response may play a role in the future treatment of MCC.

Staging and Prognosis

Due to the extremely aggressive nature of MCC, patients with local disease and tumors 2 cm or smaller in diameter have a 66% survival at 5 years.^1,3 The 5-year survival rate for patients with local metastasis to regional lymph nodes ranges from 26% to 42%. Patients with distant metastasis have an 18% survival rate at 5 years.^1,3 Data suggest that sentinel lymph node biopsy should be performed on all patients with MCC regardless of tumor size.¹ There are no consensus guidelines to date regarding imaging for the staging of MCC patients. It is suggested that (18F)fluorodeoxyglucose positron emission tomography alone or in combination with computed tomography (CT) may be of value as a single whole-body diagnostic tool for accurate staging.¹⁰ It also has been suggested that (18F)fluorodeoxyglucose positron emission tomography and CT may offer more accurate staging than other screening modalities such as CT alone or magnetic resonance imaging.^14,19

Treatment of MCC

Surgery remains the mainstay of treatment of MCC. Current National Comprehensive Cancer Network guidelines²⁰ recommend 1- to 2-cm margins for wide local excision or treatment with Mohs micrographic surgery. Sentinel lymph node biopsy should be performed intraoperatively in patients undergoing wide local excision and preoperatively for patients undergoing Mohs micrographic surgery due to potential alterations in lymphatic drainage that may affect lymphoscintigraphy.¹

Radiation may be used as primary or adjuvant therapy in patients with MCC. Radiation as primary therapy generally is reserved for patients who are not surgical candidates. It has been suggested that there was no difference in outcome in a small group of patients treated with radiation alone compared to patients who underwent surgery and radiation to the tumor bed.¹ Current guidelines suggest a small group of patients may not require adjuvant therapy following adequate resection of some small tumors, and clinical observation may be appropriate.^1,3 Chemotherapy may play a palliative role in patients with metastatic MCC. Merkel cell carcinoma has been shown to be chemosensitive but with a high recurrence rate.¹ Because the immune system plays an important role in disease prognosis, having an intact immune system likely is paramount in the prevention of further disease progression.

Future Treatments of MCC

Future treatment of MCC may be focused on the viral etiology of most tumors and upregulation of the immune response, which may lead to the possibility of specifically interfering with virus-specific oncoproteins and stimulation of immune responses to virally infected tumor cells.⁸ The MCPyV large T antigen has been found to be overexpressed in some tumors and may serve as a specific target of therapy.^10,21 Survivin, a key cell cycle protein encoded by LT antigen, may be an interesting target given its implication in other cancers.¹³ Other potential nonviral molecular target antigens include the oncoprotein H1P1 that interacts with c-KIT.⁸ Specific immunostimulatory cytokines that may be used to upregulate the immune response to tumoral cells may include IL-2, IL-12, IL-15, or IL-21. Therapeutic agents that may be studied in the future to target the immune exhaustion phenomenon associated with tumorigenesis include ipilimumab (cytotoxic T lymphocyte antigen 4 receptor-blocking agent) as well as programmed cell death 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1).⁸ Neuroendocrine tumors including MCC tend to be highly vascular and express vascular endothelial growth factors and platelet-derived growth factors, which may be other potential therapeutic targets. It has been reported that approximately 95% of MCC patients have CD56⁺ tumors, and current clinical trials suggest a promising therapeutic response with the immunogen anti-CD56 monoclonal antibody.³

Conclusion

Merkel cell carcinoma is a rare aggressive neuroendocrine tumor that has been associated with a novel polyomavirus. Merkel cell carcinoma tends to affect elderly and immunocompromised patients as well as white individuals. Tumors are most often found in areas of high UV exposure and clinically on sun-exposed skin. Merkel cell polyomavirus is associated with approximately 80% of tumors, and tumorigenesis likely is caused by a number of sequential steps from viral integration into host DNA, mutagenic events, and specific immune responses. Currently there are no consensus guidelines for using imaging for staging of MCCs, but sentinel lymph node biopsy is recommended for all cases due to the aggressive nature of even smaller tumors. Surgery remains the mainstay of treatment, and radiation therapy may be used as a primary or adjuvant treatment. Chemotherapy usually is reserved for patients with metastatic disease purely for palliation. Future treatments of MCC likely will center on the viral etiology of MCC and upregulation of immune responses to virally infected tumor cells.

The best diagnosis is:

a. bronchogenic cyst
b. dermoid cyst
c. epidermal inclusion cyst
d. hidrocystoma
e. steatocystoma

H&E, original magnification ×40.

H&E, original magnification ×100.

Continue to the next page for the diagnosis >>

Dermoid Cyst

Dermoid cysts often present clinically as firm subcutaneous nodules on the head or neck in young children. They tend to arise along the lateral aspect of the eyebrow but also can occur on the nose, forehead, neck, chest, or scalp.¹ Dermoid cysts are thought to arise from the sequestration of ectodermal tissues along the embryonic fusion planes during development.² As such, they represent congenital defects and often are identified at birth; however, some are not noticed until much later when they enlarge or become inflamed or infected. Midline dermoid cysts may be associated with underlying dysraphism or intracranial extension.^3,4 Thus, any midline lesion warrants evaluation that incorporates imaging with computed tomography or magnetic resonance imaging.^4,5 Histologically, dermoid cysts are lined by a keratinizing stratified squamous epithelium (quiz image A), but the lining may be brightly eosinophilic and wavy resembling shark teeth.^1,3 The wall of a dermoid cyst commonly contains mature adnexal structures such as terminal hair follicles, sebaceous glands, apocrine glands, and/or eccrine glands (quiz image B).¹ Smooth muscle also may be seen within the lining; however, bone and cartilage are not commonly reported in dermoid cysts.² Lamellar keratin is typical of the cyst contents, and terminal hair shafts also are sometimes noted within the cystic space (quiz image B).^1,2 Treatment options include excision at the time of diagnosis or close clinical monitoring with subsequent excision if the lesion grows or becomes symptomatic.^4,5 Many practitioners opt to excise these cysts at diagnosis, as untreated lesions are at risk for infection and/or inflammation or may be cosmetically deforming.^6,7 Surgical resection, including removal of the wall of the cyst, is curative and reoccurrence is rare.⁵

Figure 1. Bronchogenic cyst demonstrating a ciliated pseudostratified epithelial lining encircled by smooth muscle (H&E, original magnification ×200).
Figure 2. Epidermal inclusion cyst containing loose lamellar keratin and a lining that closely resembles the surface epidermis (H&E, original magnification ×40).

Bronchogenic cysts demonstrate an epithelial lining that often is pseudostratified cuboidal or columnar as well as ciliated (Figure 1). Goblet cells are present in the lining in approximately 50% of cases. Smooth muscle may be seen circumferentially surrounding the cyst lining, and rare cases also contain cartilage.¹ In contrast to dermoid cysts, other types of adnexal structures are not found within the lining. Bronchogenic cysts that arise in the skin are extremely rare.² These cysts are thought to arise from respiratory epithelium that has been sequestered during embryologic formation of the tracheobronchial tree. They often are seen overlying the suprasternal notch and occasionally are found on the anterior aspect of the neck or chin. These cysts also are present at birth, similar to dermoid cysts.³

Epidermal inclusion cysts have a lining that histologically bears close resemblance to the surface epidermis. These cysts contain loose lamellar keratin, similar to a dermoid cyst. In contrast, the lining of an epidermal inclusion cyst will lack adnexal structures (Figure 2).¹ Clinically, epidermal inclusion cysts often present as smooth, dome-shaped papules and nodules with a central punctum. They are classically found on the face, neck, and trunk. These cysts are thought to arise after a traumatic insult to the pilosebaceous unit.²

Hidrocystomas can be apocrine or eccrine.³ Eccrine hidrocystomas are unilocular cysts that are lined by 2 layers of flattened to cuboidal epithelial cells (Figure 3). The cysts are filled with clear fluid and often are found adjacent to normal eccrine glands.¹ Apocrine hidrocystomas are unilocular or multilocular cysts that are lined by 1 to several layers of epithelial cells. The lining of an apocrine hidrocystoma will often exhibit luminal decapitation secretion.³ Apocrine and eccrine hidrocystomas are clinically identical and appear as blue translucent papules on the cheeks or eyelids of adults.^1-3 They usually occur periorbitally but also can be seen on the trunk, popliteal fossa, external ears, or vulva. Eccrine hidrocystomas can wax and wane in accordance with the amount of sweat produced; thus, they often expand in size during the summer months.²

Steatocystomas, or simple sebaceous duct cysts, histologically demonstrate a characteristically wavy and eosinophilic cuticle resembling shark teeth (Figure 4) similar to the lining of the sebaceous duct where it enters the follicle.¹ Sebaceous glands are an almost invariable feature, either present within the lining of the cyst (Figure 4) or in the adjacent tissue.² In comparison, dermoid cysts may have a red wavy cuticle but also will usually have terminal hair follicles or eccrine or apocrine glands within the wall of the cyst. Steatocystomas typically are collapsed and empty or only contain sebaceous debris (Figure 4) rather than the lamellar keratin seen in dermoid and epidermoid inclusion cysts. Steatocystomas can occur as solitary (steatocystoma simplex) or multiple (steatocystoma multiplex) lesions.^1,3 They are clinically comprised of small dome-shaped papules that often are translucent and yellow. These cysts are commonly found on the sternum of males and the axillae or groin of females.²

Figure 3. Eccrine hidrocystoma with clear contents and lined by 2 layers of cuboidal epithelial cells (H&E, original magnification ×100).		Figure 4. Steatocystoma with a red wavy cuticle, sparse sebaceous contents, and sebaceous glands within the lining (H&E, original magnification ×100).

The best diagnosis is:

a. bronchogenic cyst
b. dermoid cyst
c. epidermal inclusion cyst
d. hidrocystoma
e. steatocystoma

H&E, original magnification ×40.

H&E, original magnification ×100.

Continue to the next page for the diagnosis >>

Dermoid Cyst

Dermoid cysts often present clinically as firm subcutaneous nodules on the head or neck in young children. They tend to arise along the lateral aspect of the eyebrow but also can occur on the nose, forehead, neck, chest, or scalp.¹ Dermoid cysts are thought to arise from the sequestration of ectodermal tissues along the embryonic fusion planes during development.² As such, they represent congenital defects and often are identified at birth; however, some are not noticed until much later when they enlarge or become inflamed or infected. Midline dermoid cysts may be associated with underlying dysraphism or intracranial extension.^3,4 Thus, any midline lesion warrants evaluation that incorporates imaging with computed tomography or magnetic resonance imaging.^4,5 Histologically, dermoid cysts are lined by a keratinizing stratified squamous epithelium (quiz image A), but the lining may be brightly eosinophilic and wavy resembling shark teeth.^1,3 The wall of a dermoid cyst commonly contains mature adnexal structures such as terminal hair follicles, sebaceous glands, apocrine glands, and/or eccrine glands (quiz image B).¹ Smooth muscle also may be seen within the lining; however, bone and cartilage are not commonly reported in dermoid cysts.² Lamellar keratin is typical of the cyst contents, and terminal hair shafts also are sometimes noted within the cystic space (quiz image B).^1,2 Treatment options include excision at the time of diagnosis or close clinical monitoring with subsequent excision if the lesion grows or becomes symptomatic.^4,5 Many practitioners opt to excise these cysts at diagnosis, as untreated lesions are at risk for infection and/or inflammation or may be cosmetically deforming.^6,7 Surgical resection, including removal of the wall of the cyst, is curative and reoccurrence is rare.⁵

Figure 1. Bronchogenic cyst demonstrating a ciliated pseudostratified epithelial lining encircled by smooth muscle (H&E, original magnification ×200).
Figure 2. Epidermal inclusion cyst containing loose lamellar keratin and a lining that closely resembles the surface epidermis (H&E, original magnification ×40).

Bronchogenic cysts demonstrate an epithelial lining that often is pseudostratified cuboidal or columnar as well as ciliated (Figure 1). Goblet cells are present in the lining in approximately 50% of cases. Smooth muscle may be seen circumferentially surrounding the cyst lining, and rare cases also contain cartilage.¹ In contrast to dermoid cysts, other types of adnexal structures are not found within the lining. Bronchogenic cysts that arise in the skin are extremely rare.² These cysts are thought to arise from respiratory epithelium that has been sequestered during embryologic formation of the tracheobronchial tree. They often are seen overlying the suprasternal notch and occasionally are found on the anterior aspect of the neck or chin. These cysts also are present at birth, similar to dermoid cysts.³

Epidermal inclusion cysts have a lining that histologically bears close resemblance to the surface epidermis. These cysts contain loose lamellar keratin, similar to a dermoid cyst. In contrast, the lining of an epidermal inclusion cyst will lack adnexal structures (Figure 2).¹ Clinically, epidermal inclusion cysts often present as smooth, dome-shaped papules and nodules with a central punctum. They are classically found on the face, neck, and trunk. These cysts are thought to arise after a traumatic insult to the pilosebaceous unit.²

Hidrocystomas can be apocrine or eccrine.³ Eccrine hidrocystomas are unilocular cysts that are lined by 2 layers of flattened to cuboidal epithelial cells (Figure 3). The cysts are filled with clear fluid and often are found adjacent to normal eccrine glands.¹ Apocrine hidrocystomas are unilocular or multilocular cysts that are lined by 1 to several layers of epithelial cells. The lining of an apocrine hidrocystoma will often exhibit luminal decapitation secretion.³ Apocrine and eccrine hidrocystomas are clinically identical and appear as blue translucent papules on the cheeks or eyelids of adults.^1-3 They usually occur periorbitally but also can be seen on the trunk, popliteal fossa, external ears, or vulva. Eccrine hidrocystomas can wax and wane in accordance with the amount of sweat produced; thus, they often expand in size during the summer months.²

Steatocystomas, or simple sebaceous duct cysts, histologically demonstrate a characteristically wavy and eosinophilic cuticle resembling shark teeth (Figure 4) similar to the lining of the sebaceous duct where it enters the follicle.¹ Sebaceous glands are an almost invariable feature, either present within the lining of the cyst (Figure 4) or in the adjacent tissue.² In comparison, dermoid cysts may have a red wavy cuticle but also will usually have terminal hair follicles or eccrine or apocrine glands within the wall of the cyst. Steatocystomas typically are collapsed and empty or only contain sebaceous debris (Figure 4) rather than the lamellar keratin seen in dermoid and epidermoid inclusion cysts. Steatocystomas can occur as solitary (steatocystoma simplex) or multiple (steatocystoma multiplex) lesions.^1,3 They are clinically comprised of small dome-shaped papules that often are translucent and yellow. These cysts are commonly found on the sternum of males and the axillae or groin of females.²

Figure 3. Eccrine hidrocystoma with clear contents and lined by 2 layers of cuboidal epithelial cells (H&E, original magnification ×100).		Figure 4. Steatocystoma with a red wavy cuticle, sparse sebaceous contents, and sebaceous glands within the lining (H&E, original magnification ×100).

The best diagnosis is:

a. bronchogenic cyst
b. dermoid cyst
c. epidermal inclusion cyst
d. hidrocystoma
e. steatocystoma

H&E, original magnification ×40.

H&E, original magnification ×100.

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Dermoid Cyst

Dermoid cysts often present clinically as firm subcutaneous nodules on the head or neck in young children. They tend to arise along the lateral aspect of the eyebrow but also can occur on the nose, forehead, neck, chest, or scalp.¹ Dermoid cysts are thought to arise from the sequestration of ectodermal tissues along the embryonic fusion planes during development.² As such, they represent congenital defects and often are identified at birth; however, some are not noticed until much later when they enlarge or become inflamed or infected. Midline dermoid cysts may be associated with underlying dysraphism or intracranial extension.^3,4 Thus, any midline lesion warrants evaluation that incorporates imaging with computed tomography or magnetic resonance imaging.^4,5 Histologically, dermoid cysts are lined by a keratinizing stratified squamous epithelium (quiz image A), but the lining may be brightly eosinophilic and wavy resembling shark teeth.^1,3 The wall of a dermoid cyst commonly contains mature adnexal structures such as terminal hair follicles, sebaceous glands, apocrine glands, and/or eccrine glands (quiz image B).¹ Smooth muscle also may be seen within the lining; however, bone and cartilage are not commonly reported in dermoid cysts.² Lamellar keratin is typical of the cyst contents, and terminal hair shafts also are sometimes noted within the cystic space (quiz image B).^1,2 Treatment options include excision at the time of diagnosis or close clinical monitoring with subsequent excision if the lesion grows or becomes symptomatic.^4,5 Many practitioners opt to excise these cysts at diagnosis, as untreated lesions are at risk for infection and/or inflammation or may be cosmetically deforming.^6,7 Surgical resection, including removal of the wall of the cyst, is curative and reoccurrence is rare.⁵

Figure 1. Bronchogenic cyst demonstrating a ciliated pseudostratified epithelial lining encircled by smooth muscle (H&E, original magnification ×200).
Figure 2. Epidermal inclusion cyst containing loose lamellar keratin and a lining that closely resembles the surface epidermis (H&E, original magnification ×40).

Bronchogenic cysts demonstrate an epithelial lining that often is pseudostratified cuboidal or columnar as well as ciliated (Figure 1). Goblet cells are present in the lining in approximately 50% of cases. Smooth muscle may be seen circumferentially surrounding the cyst lining, and rare cases also contain cartilage.¹ In contrast to dermoid cysts, other types of adnexal structures are not found within the lining. Bronchogenic cysts that arise in the skin are extremely rare.² These cysts are thought to arise from respiratory epithelium that has been sequestered during embryologic formation of the tracheobronchial tree. They often are seen overlying the suprasternal notch and occasionally are found on the anterior aspect of the neck or chin. These cysts also are present at birth, similar to dermoid cysts.³

Epidermal inclusion cysts have a lining that histologically bears close resemblance to the surface epidermis. These cysts contain loose lamellar keratin, similar to a dermoid cyst. In contrast, the lining of an epidermal inclusion cyst will lack adnexal structures (Figure 2).¹ Clinically, epidermal inclusion cysts often present as smooth, dome-shaped papules and nodules with a central punctum. They are classically found on the face, neck, and trunk. These cysts are thought to arise after a traumatic insult to the pilosebaceous unit.²

Hidrocystomas can be apocrine or eccrine.³ Eccrine hidrocystomas are unilocular cysts that are lined by 2 layers of flattened to cuboidal epithelial cells (Figure 3). The cysts are filled with clear fluid and often are found adjacent to normal eccrine glands.¹ Apocrine hidrocystomas are unilocular or multilocular cysts that are lined by 1 to several layers of epithelial cells. The lining of an apocrine hidrocystoma will often exhibit luminal decapitation secretion.³ Apocrine and eccrine hidrocystomas are clinically identical and appear as blue translucent papules on the cheeks or eyelids of adults.^1-3 They usually occur periorbitally but also can be seen on the trunk, popliteal fossa, external ears, or vulva. Eccrine hidrocystomas can wax and wane in accordance with the amount of sweat produced; thus, they often expand in size during the summer months.²

Steatocystomas, or simple sebaceous duct cysts, histologically demonstrate a characteristically wavy and eosinophilic cuticle resembling shark teeth (Figure 4) similar to the lining of the sebaceous duct where it enters the follicle.¹ Sebaceous glands are an almost invariable feature, either present within the lining of the cyst (Figure 4) or in the adjacent tissue.² In comparison, dermoid cysts may have a red wavy cuticle but also will usually have terminal hair follicles or eccrine or apocrine glands within the wall of the cyst. Steatocystomas typically are collapsed and empty or only contain sebaceous debris (Figure 4) rather than the lamellar keratin seen in dermoid and epidermoid inclusion cysts. Steatocystomas can occur as solitary (steatocystoma simplex) or multiple (steatocystoma multiplex) lesions.^1,3 They are clinically comprised of small dome-shaped papules that often are translucent and yellow. These cysts are commonly found on the sternum of males and the axillae or groin of females.²

Figure 3. Eccrine hidrocystoma with clear contents and lined by 2 layers of cuboidal epithelial cells (H&E, original magnification ×100).		Figure 4. Steatocystoma with a red wavy cuticle, sparse sebaceous contents, and sebaceous glands within the lining (H&E, original magnification ×100).

Onychomatricoma (OM) is a rare benign neoplasm of the nail matrix. Even less common is its possible association with both trauma to the nail apparatus and onychomycosis. This case illustrates both of these findings.

Case Report
A 72-year-old white man presented to the dermatology clinic with a 26-year history of a thickened nail plate on the right third finger that had developed soon after a baseball injury. The patient reported that the nail was completely normal prior to the trauma. According to the patient, the distal aspect of the finger was directly hit by a baseball and subsequently was wrapped by the patient for a few weeks. The nail then turned black and eventually fell off. When the nail grew back, it appeared abnormal and in its current state. The patient stated the lesion was asymptomatic at the time of presentation.

Physical examination revealed thickening, yellow discoloration, and transverse overcurvature of the nail plate on the right third finger with longitudinal ridging (Figure 1). A culture of the nail plate grew Chaetomium species. Application of topical clotrimazole for 3 months followed by a 6-week course of oral terbinafine produced no improvement. The patient then consented to a nail matrix incisional biopsy 6 months after initial presentation. After a digital nerve block was administered and a tourniquet of the proximal digit was applied, a nail avulsion was performed. Subsequently, a 3-mm punch biopsy was taken of the clinically apparent tumor in the nail matrix.

On microscopic examination of the removed tissue, a benign mixed epithelial and stromal proliferative lesion was noted. The basaloid epithelium, lacking a granular layer, arose from the surface epithelial layer and formed a reticulated pattern extending into the stromal component, which was moderately cellular with spindle to fusiform nuclei dissecting between collagen bundles arranged in parallel arrays (Figure 2). The stromal component predominated over the epithelial component in this neoplasm. The nail was preserved in formalin and underwent hematoxylin and eosin staining. It was thickened and grossly showed filiform fibrous projections extending into the nail plate. Histologically, the nail displayed prominent oval clear channels. Periodic acid–Schiff staining was negative for fungal organisms.

A diagnosis of unguioblastic fibroma–type OM was made. After receiving the diagnosis, expected course, and treatment options, the patient was offered conservative surgical excision but preferred clinical monitoring. At his last visit (6 months after the biopsy), the nail plate distal to the biopsy site had thinning and improvement, while the nail plate distal to the matrix that was not removed continued to show thickening, yellow discoloration, overcurvature, and longitudinal ridging (Figure 3).

Figure 2. The basaloid epithelium arose from the surface epithelial layer and formed a reticulated pattern extending into the stromal component (A)(H&E, original magnification ×2). At higher magnification, the stromal component was moderately cellular with spindle to fusiform nuclei dissecting between collagen bundles arranged in parallel arrays (B)(H&E, original magnification ×10).

Comment
Onychomatricoma is a rare tumor originating from the nail matrix. The tumor was first described by Baran and Kint¹ in 1992 using the term onychomatrixoma, but later the term onychomatricoma became more widely used.² Onychomatricomas are more common in adults (mean age, 48 years) and white individuals with no gender predilection.^3,4 Fingernail involvement is twice as common as toenail involvement.³ Onychomatricoma is the only tumor that actively produces a nail plate.⁴

Clinically, OM presents with yellow discoloration along the entire nail plate and proximal splinter hemorrhages. It has a tendency toward transverse overcurvature of the nail plate with prominent longitudinal ridging.⁴ Trauma has been associated in at least 3 cases reported in the literature, though the association was sometimes weak.^3,4 Xanthonychia and onychodystrophy of the nail are common.³ Pterygium, melanonychia, nail bleeding, and cutaneous horns have been reported but are rare.^3-5 The tumor typically is painless with no radiographic bone involvement.³ Onychomycosis can be present,³ which may either be a predisposing factor for the tumor or secondary due to the deformed nail plate.⁴

When the nail plate is avulsed and the proximal nail fold is turned back, the matrix tumor is exposed. This polypoid and filiform tumor has characteristic fingerlike fibrokeratogenous projections extending from the nail matrix into the nail plate.³

Histologically, the tumor is fibroepithelial or biphasic with stromal and epithelial components. It has a lobulated and papillary growth pattern with 2 distinct areas that correspond to 2 anatomic zones.³ The base of the tumor corresponds to the proximal anatomic zone, which begins at the root of the nail and extends to the cuticle. This area is composed of V-shaped keratinous zones similar to the normal matrix. If the nail is removed prior to excision, these areas can be avulsed, leaving clear clefts. The superficial aspect of the tumor corresponds to the distal anatomic zone, which is located in the region of the lunula. This area is composed of multiple digitate or fingerlike projections with a fibrous core and a thick matrical epithelial covering.³ These digitations extend into small cavities in the nail plate, which can be visualized as clear channels or woodwormlike holes in hematoxylin and eosin–stained specimens. A biphasic fibrous stroma also can be observed with the superficial dermis being cellular with fibrillary collagen and the deep dermis more hypocellular with thicker collagen bundles.^3,4

An analysis of keratins in the nail matrix, bed, and isthmus showed that OM has the capacity to recapitulate the entire nail unit with differentiation toward the nail bed and isthmus.⁶ It appears that the mesenchymal component has an inductive effect that can lead to complete epithelial onychogenic differentiation.⁶

Due to the histological differences among the described cases of OM in the literature, a new classification based on the spectrum of epithelial to stromal ratio of stromal cellularity and the extent of nuclear pleomorphism was proposed in 2004.⁷ The prominent feature of the unguioblastoma type of OM is epithelial, while the cellular stroma is the prominent feature in the unguioblastic fibroma type. Atypical unguioblastic fibroma refers to a tumor with increased mitotic activity and nuclear pleomorphism among the stroma.⁷

Most OM tumors follow a benign clinical course; however, complete excision is advised to include the normal nail matrix proximal to the lesion, which may prevent recurrence and serves as a primary treatment.

Conclusion
Onychomatricoma is a benign neoplasm of the nail matrix that may be triggered by trauma; however, due to the weak association, further observations and studies should be conducted to substantiate this possibility. Patients with the classic clinical presentation possibly may be spared a nail avulsion and biopsy. Onychomycosis occurs in the setting of OM, and culture and treatment are unlikely to change the appearance or course of this nail condition.

Onychomatricoma (OM) is a rare benign neoplasm of the nail matrix. Even less common is its possible association with both trauma to the nail apparatus and onychomycosis. This case illustrates both of these findings.

Case Report
A 72-year-old white man presented to the dermatology clinic with a 26-year history of a thickened nail plate on the right third finger that had developed soon after a baseball injury. The patient reported that the nail was completely normal prior to the trauma. According to the patient, the distal aspect of the finger was directly hit by a baseball and subsequently was wrapped by the patient for a few weeks. The nail then turned black and eventually fell off. When the nail grew back, it appeared abnormal and in its current state. The patient stated the lesion was asymptomatic at the time of presentation.

Physical examination revealed thickening, yellow discoloration, and transverse overcurvature of the nail plate on the right third finger with longitudinal ridging (Figure 1). A culture of the nail plate grew Chaetomium species. Application of topical clotrimazole for 3 months followed by a 6-week course of oral terbinafine produced no improvement. The patient then consented to a nail matrix incisional biopsy 6 months after initial presentation. After a digital nerve block was administered and a tourniquet of the proximal digit was applied, a nail avulsion was performed. Subsequently, a 3-mm punch biopsy was taken of the clinically apparent tumor in the nail matrix.

On microscopic examination of the removed tissue, a benign mixed epithelial and stromal proliferative lesion was noted. The basaloid epithelium, lacking a granular layer, arose from the surface epithelial layer and formed a reticulated pattern extending into the stromal component, which was moderately cellular with spindle to fusiform nuclei dissecting between collagen bundles arranged in parallel arrays (Figure 2). The stromal component predominated over the epithelial component in this neoplasm. The nail was preserved in formalin and underwent hematoxylin and eosin staining. It was thickened and grossly showed filiform fibrous projections extending into the nail plate. Histologically, the nail displayed prominent oval clear channels. Periodic acid–Schiff staining was negative for fungal organisms.

A diagnosis of unguioblastic fibroma–type OM was made. After receiving the diagnosis, expected course, and treatment options, the patient was offered conservative surgical excision but preferred clinical monitoring. At his last visit (6 months after the biopsy), the nail plate distal to the biopsy site had thinning and improvement, while the nail plate distal to the matrix that was not removed continued to show thickening, yellow discoloration, overcurvature, and longitudinal ridging (Figure 3).

Figure 2. The basaloid epithelium arose from the surface epithelial layer and formed a reticulated pattern extending into the stromal component (A)(H&E, original magnification ×2). At higher magnification, the stromal component was moderately cellular with spindle to fusiform nuclei dissecting between collagen bundles arranged in parallel arrays (B)(H&E, original magnification ×10).

Comment
Onychomatricoma is a rare tumor originating from the nail matrix. The tumor was first described by Baran and Kint¹ in 1992 using the term onychomatrixoma, but later the term onychomatricoma became more widely used.² Onychomatricomas are more common in adults (mean age, 48 years) and white individuals with no gender predilection.^3,4 Fingernail involvement is twice as common as toenail involvement.³ Onychomatricoma is the only tumor that actively produces a nail plate.⁴

Clinically, OM presents with yellow discoloration along the entire nail plate and proximal splinter hemorrhages. It has a tendency toward transverse overcurvature of the nail plate with prominent longitudinal ridging.⁴ Trauma has been associated in at least 3 cases reported in the literature, though the association was sometimes weak.^3,4 Xanthonychia and onychodystrophy of the nail are common.³ Pterygium, melanonychia, nail bleeding, and cutaneous horns have been reported but are rare.^3-5 The tumor typically is painless with no radiographic bone involvement.³ Onychomycosis can be present,³ which may either be a predisposing factor for the tumor or secondary due to the deformed nail plate.⁴

When the nail plate is avulsed and the proximal nail fold is turned back, the matrix tumor is exposed. This polypoid and filiform tumor has characteristic fingerlike fibrokeratogenous projections extending from the nail matrix into the nail plate.³

Histologically, the tumor is fibroepithelial or biphasic with stromal and epithelial components. It has a lobulated and papillary growth pattern with 2 distinct areas that correspond to 2 anatomic zones.³ The base of the tumor corresponds to the proximal anatomic zone, which begins at the root of the nail and extends to the cuticle. This area is composed of V-shaped keratinous zones similar to the normal matrix. If the nail is removed prior to excision, these areas can be avulsed, leaving clear clefts. The superficial aspect of the tumor corresponds to the distal anatomic zone, which is located in the region of the lunula. This area is composed of multiple digitate or fingerlike projections with a fibrous core and a thick matrical epithelial covering.³ These digitations extend into small cavities in the nail plate, which can be visualized as clear channels or woodwormlike holes in hematoxylin and eosin–stained specimens. A biphasic fibrous stroma also can be observed with the superficial dermis being cellular with fibrillary collagen and the deep dermis more hypocellular with thicker collagen bundles.^3,4

An analysis of keratins in the nail matrix, bed, and isthmus showed that OM has the capacity to recapitulate the entire nail unit with differentiation toward the nail bed and isthmus.⁶ It appears that the mesenchymal component has an inductive effect that can lead to complete epithelial onychogenic differentiation.⁶

Due to the histological differences among the described cases of OM in the literature, a new classification based on the spectrum of epithelial to stromal ratio of stromal cellularity and the extent of nuclear pleomorphism was proposed in 2004.⁷ The prominent feature of the unguioblastoma type of OM is epithelial, while the cellular stroma is the prominent feature in the unguioblastic fibroma type. Atypical unguioblastic fibroma refers to a tumor with increased mitotic activity and nuclear pleomorphism among the stroma.⁷

Most OM tumors follow a benign clinical course; however, complete excision is advised to include the normal nail matrix proximal to the lesion, which may prevent recurrence and serves as a primary treatment.

Conclusion
Onychomatricoma is a benign neoplasm of the nail matrix that may be triggered by trauma; however, due to the weak association, further observations and studies should be conducted to substantiate this possibility. Patients with the classic clinical presentation possibly may be spared a nail avulsion and biopsy. Onychomycosis occurs in the setting of OM, and culture and treatment are unlikely to change the appearance or course of this nail condition.

Onychomatricoma (OM) is a rare benign neoplasm of the nail matrix. Even less common is its possible association with both trauma to the nail apparatus and onychomycosis. This case illustrates both of these findings.

Case Report
A 72-year-old white man presented to the dermatology clinic with a 26-year history of a thickened nail plate on the right third finger that had developed soon after a baseball injury. The patient reported that the nail was completely normal prior to the trauma. According to the patient, the distal aspect of the finger was directly hit by a baseball and subsequently was wrapped by the patient for a few weeks. The nail then turned black and eventually fell off. When the nail grew back, it appeared abnormal and in its current state. The patient stated the lesion was asymptomatic at the time of presentation.

Physical examination revealed thickening, yellow discoloration, and transverse overcurvature of the nail plate on the right third finger with longitudinal ridging (Figure 1). A culture of the nail plate grew Chaetomium species. Application of topical clotrimazole for 3 months followed by a 6-week course of oral terbinafine produced no improvement. The patient then consented to a nail matrix incisional biopsy 6 months after initial presentation. After a digital nerve block was administered and a tourniquet of the proximal digit was applied, a nail avulsion was performed. Subsequently, a 3-mm punch biopsy was taken of the clinically apparent tumor in the nail matrix.

On microscopic examination of the removed tissue, a benign mixed epithelial and stromal proliferative lesion was noted. The basaloid epithelium, lacking a granular layer, arose from the surface epithelial layer and formed a reticulated pattern extending into the stromal component, which was moderately cellular with spindle to fusiform nuclei dissecting between collagen bundles arranged in parallel arrays (Figure 2). The stromal component predominated over the epithelial component in this neoplasm. The nail was preserved in formalin and underwent hematoxylin and eosin staining. It was thickened and grossly showed filiform fibrous projections extending into the nail plate. Histologically, the nail displayed prominent oval clear channels. Periodic acid–Schiff staining was negative for fungal organisms.

A diagnosis of unguioblastic fibroma–type OM was made. After receiving the diagnosis, expected course, and treatment options, the patient was offered conservative surgical excision but preferred clinical monitoring. At his last visit (6 months after the biopsy), the nail plate distal to the biopsy site had thinning and improvement, while the nail plate distal to the matrix that was not removed continued to show thickening, yellow discoloration, overcurvature, and longitudinal ridging (Figure 3).

Figure 2. The basaloid epithelium arose from the surface epithelial layer and formed a reticulated pattern extending into the stromal component (A)(H&E, original magnification ×2). At higher magnification, the stromal component was moderately cellular with spindle to fusiform nuclei dissecting between collagen bundles arranged in parallel arrays (B)(H&E, original magnification ×10).

Comment
Onychomatricoma is a rare tumor originating from the nail matrix. The tumor was first described by Baran and Kint¹ in 1992 using the term onychomatrixoma, but later the term onychomatricoma became more widely used.² Onychomatricomas are more common in adults (mean age, 48 years) and white individuals with no gender predilection.^3,4 Fingernail involvement is twice as common as toenail involvement.³ Onychomatricoma is the only tumor that actively produces a nail plate.⁴

Clinically, OM presents with yellow discoloration along the entire nail plate and proximal splinter hemorrhages. It has a tendency toward transverse overcurvature of the nail plate with prominent longitudinal ridging.⁴ Trauma has been associated in at least 3 cases reported in the literature, though the association was sometimes weak.^3,4 Xanthonychia and onychodystrophy of the nail are common.³ Pterygium, melanonychia, nail bleeding, and cutaneous horns have been reported but are rare.^3-5 The tumor typically is painless with no radiographic bone involvement.³ Onychomycosis can be present,³ which may either be a predisposing factor for the tumor or secondary due to the deformed nail plate.⁴

When the nail plate is avulsed and the proximal nail fold is turned back, the matrix tumor is exposed. This polypoid and filiform tumor has characteristic fingerlike fibrokeratogenous projections extending from the nail matrix into the nail plate.³

Histologically, the tumor is fibroepithelial or biphasic with stromal and epithelial components. It has a lobulated and papillary growth pattern with 2 distinct areas that correspond to 2 anatomic zones.³ The base of the tumor corresponds to the proximal anatomic zone, which begins at the root of the nail and extends to the cuticle. This area is composed of V-shaped keratinous zones similar to the normal matrix. If the nail is removed prior to excision, these areas can be avulsed, leaving clear clefts. The superficial aspect of the tumor corresponds to the distal anatomic zone, which is located in the region of the lunula. This area is composed of multiple digitate or fingerlike projections with a fibrous core and a thick matrical epithelial covering.³ These digitations extend into small cavities in the nail plate, which can be visualized as clear channels or woodwormlike holes in hematoxylin and eosin–stained specimens. A biphasic fibrous stroma also can be observed with the superficial dermis being cellular with fibrillary collagen and the deep dermis more hypocellular with thicker collagen bundles.^3,4

An analysis of keratins in the nail matrix, bed, and isthmus showed that OM has the capacity to recapitulate the entire nail unit with differentiation toward the nail bed and isthmus.⁶ It appears that the mesenchymal component has an inductive effect that can lead to complete epithelial onychogenic differentiation.⁶

Due to the histological differences among the described cases of OM in the literature, a new classification based on the spectrum of epithelial to stromal ratio of stromal cellularity and the extent of nuclear pleomorphism was proposed in 2004.⁷ The prominent feature of the unguioblastoma type of OM is epithelial, while the cellular stroma is the prominent feature in the unguioblastic fibroma type. Atypical unguioblastic fibroma refers to a tumor with increased mitotic activity and nuclear pleomorphism among the stroma.⁷

Most OM tumors follow a benign clinical course; however, complete excision is advised to include the normal nail matrix proximal to the lesion, which may prevent recurrence and serves as a primary treatment.

Conclusion
Onychomatricoma is a benign neoplasm of the nail matrix that may be triggered by trauma; however, due to the weak association, further observations and studies should be conducted to substantiate this possibility. Patients with the classic clinical presentation possibly may be spared a nail avulsion and biopsy. Onychomycosis occurs in the setting of OM, and culture and treatment are unlikely to change the appearance or course of this nail condition.

To the Editor:

Figure 1. A 30-cm pink and violaceous, asymmetric, reticulated patch on the lateral aspect of the right thigh.

Figure 2. Histopathology revealed widely dilated vascular channels containing collections of histiocytes in the superficial dermis with adjacent features of chronic lymphedema (A)(H&E, original magnification ×10) as well as a collection of histiocytes in a dilated lymphatic channel (B)(H&E, original magnification ×40). D2-40 staining demonstrated ectatic lymphatic vessels in the upper dermins (C)(original magnification ×20).

A 70-year-old white man presented with an asymptomatic patch on the lateral aspect of the right thigh of 15 months’ duration. The patient believed the patch correlated with a hip replacement 3 years prior; however, it was 6 inches inferior to the incision site. Physical examination revealed a 30-cm pink and violaceous, asymmetric, reticulated patch (Figure 1). The patch was unresponsive to topical corticosteroids as well as a short course of oral prednisone. The patient’s medical history was notable for type 2 diabetes mellitus. Histopathologic examination revealed widely dilated vascular channels containing collections of histiocytes in the superficial dermis. In addition, adjacent features of chronic lymphedema were present, namely interstitial fibroplasia with dilated lymphatic vessels and a lymphoplasmacytic infiltrate (Figure 2). These findings were consistent with intralymphatic histiocytosis, a rare disease most commonly associated with rheumatoid arthritis. Our patient did not have a history or clinical symptoms of rheumatoid arthritis.

Intralymphatic histiocytosis is a rare cutaneous condition reported by O’Grady et al¹ in 1994. This condition has been most frequently associated with rheumatoid arthritis²; however, there has been an emerging association in patients with orthopedic metal implants, with and without a concomitant diagnosis of rheumatoid arthritis. Cases associated with metal implants are rare.^2-7

The condition presents as asymptomatic red, brown, or violaceous patches, plaques, papules, or nodules that are ill defined and tend to demonstrate a livedo reticularis–like pattern. The lesions typically are overlying or in close proximity to a joint. Histopathologic findings include dilated vascular structures in the reticular dermis, some with empty lumina and others containing collections of mononuclear histiocytes. There also may be an inflammatory infiltrate in the adjacent dermis composed of a mix of lymphocytes, plasma cells, and/or histiocytes. Endothelial cells lining the dilated lumina express immunoreactivity for CD31, CD34, D2-40, Lyve-1, and Prox-1. Intravascular histiocytes are positive for CD68 and CD31.⁶

The pathogenesis of intralymphatic histiocytosis remains undefined. Some hypothesize that intralymphatic histiocytosis could be the early stage of reactive angioendotheliomatosis, as these conditions share clinical and histological features.⁸ Reactive angioendotheliomatosis also is a rare condition that may present as erythematous to violaceous patches or plaques. The lesions are commonly found on the limbs and may be associated with constitutional symptoms. Histologic findings of reactive angioendotheliomatosis include a proliferation of epithelioid, round, or spindle-shaped cells within the lumina of dermal blood vessels, which show positivity for CD31 and CD34.⁹ Others suggest the lesions of intralymphatic histiocytosis arise from lymphangiectasia; obstruction of lymphatic drainage due to congenital abnormalities; or acquired damage from infection, trauma, surgery, or radiation.² Due to the common association with rheumatoid arthritis and orthopedic implants, it is likely that lymphatic stasis secondary to chronic inflammation plays a notable role.

Therapies such as topical and systemic corticosteroids, local radiotherapy, cyclophosphamide, pentoxifylline, and arthrocentesis have been attempted without evidence of efficacy.² Although intralymphatic histiocytosis is chronic and resistant to therapy, patients can be reassured that the condition runs a benign course.

To the Editor:

Figure 1. A 30-cm pink and violaceous, asymmetric, reticulated patch on the lateral aspect of the right thigh.

Figure 2. Histopathology revealed widely dilated vascular channels containing collections of histiocytes in the superficial dermis with adjacent features of chronic lymphedema (A)(H&E, original magnification ×10) as well as a collection of histiocytes in a dilated lymphatic channel (B)(H&E, original magnification ×40). D2-40 staining demonstrated ectatic lymphatic vessels in the upper dermins (C)(original magnification ×20).

A 70-year-old white man presented with an asymptomatic patch on the lateral aspect of the right thigh of 15 months’ duration. The patient believed the patch correlated with a hip replacement 3 years prior; however, it was 6 inches inferior to the incision site. Physical examination revealed a 30-cm pink and violaceous, asymmetric, reticulated patch (Figure 1). The patch was unresponsive to topical corticosteroids as well as a short course of oral prednisone. The patient’s medical history was notable for type 2 diabetes mellitus. Histopathologic examination revealed widely dilated vascular channels containing collections of histiocytes in the superficial dermis. In addition, adjacent features of chronic lymphedema were present, namely interstitial fibroplasia with dilated lymphatic vessels and a lymphoplasmacytic infiltrate (Figure 2). These findings were consistent with intralymphatic histiocytosis, a rare disease most commonly associated with rheumatoid arthritis. Our patient did not have a history or clinical symptoms of rheumatoid arthritis.

Intralymphatic histiocytosis is a rare cutaneous condition reported by O’Grady et al¹ in 1994. This condition has been most frequently associated with rheumatoid arthritis²; however, there has been an emerging association in patients with orthopedic metal implants, with and without a concomitant diagnosis of rheumatoid arthritis. Cases associated with metal implants are rare.^2-7

The condition presents as asymptomatic red, brown, or violaceous patches, plaques, papules, or nodules that are ill defined and tend to demonstrate a livedo reticularis–like pattern. The lesions typically are overlying or in close proximity to a joint. Histopathologic findings include dilated vascular structures in the reticular dermis, some with empty lumina and others containing collections of mononuclear histiocytes. There also may be an inflammatory infiltrate in the adjacent dermis composed of a mix of lymphocytes, plasma cells, and/or histiocytes. Endothelial cells lining the dilated lumina express immunoreactivity for CD31, CD34, D2-40, Lyve-1, and Prox-1. Intravascular histiocytes are positive for CD68 and CD31.⁶

The pathogenesis of intralymphatic histiocytosis remains undefined. Some hypothesize that intralymphatic histiocytosis could be the early stage of reactive angioendotheliomatosis, as these conditions share clinical and histological features.⁸ Reactive angioendotheliomatosis also is a rare condition that may present as erythematous to violaceous patches or plaques. The lesions are commonly found on the limbs and may be associated with constitutional symptoms. Histologic findings of reactive angioendotheliomatosis include a proliferation of epithelioid, round, or spindle-shaped cells within the lumina of dermal blood vessels, which show positivity for CD31 and CD34.⁹ Others suggest the lesions of intralymphatic histiocytosis arise from lymphangiectasia; obstruction of lymphatic drainage due to congenital abnormalities; or acquired damage from infection, trauma, surgery, or radiation.² Due to the common association with rheumatoid arthritis and orthopedic implants, it is likely that lymphatic stasis secondary to chronic inflammation plays a notable role.

Therapies such as topical and systemic corticosteroids, local radiotherapy, cyclophosphamide, pentoxifylline, and arthrocentesis have been attempted without evidence of efficacy.² Although intralymphatic histiocytosis is chronic and resistant to therapy, patients can be reassured that the condition runs a benign course.

To the Editor:

Figure 1. A 30-cm pink and violaceous, asymmetric, reticulated patch on the lateral aspect of the right thigh.

Figure 2. Histopathology revealed widely dilated vascular channels containing collections of histiocytes in the superficial dermis with adjacent features of chronic lymphedema (A)(H&E, original magnification ×10) as well as a collection of histiocytes in a dilated lymphatic channel (B)(H&E, original magnification ×40). D2-40 staining demonstrated ectatic lymphatic vessels in the upper dermins (C)(original magnification ×20).

A 70-year-old white man presented with an asymptomatic patch on the lateral aspect of the right thigh of 15 months’ duration. The patient believed the patch correlated with a hip replacement 3 years prior; however, it was 6 inches inferior to the incision site. Physical examination revealed a 30-cm pink and violaceous, asymmetric, reticulated patch (Figure 1). The patch was unresponsive to topical corticosteroids as well as a short course of oral prednisone. The patient’s medical history was notable for type 2 diabetes mellitus. Histopathologic examination revealed widely dilated vascular channels containing collections of histiocytes in the superficial dermis. In addition, adjacent features of chronic lymphedema were present, namely interstitial fibroplasia with dilated lymphatic vessels and a lymphoplasmacytic infiltrate (Figure 2). These findings were consistent with intralymphatic histiocytosis, a rare disease most commonly associated with rheumatoid arthritis. Our patient did not have a history or clinical symptoms of rheumatoid arthritis.

Intralymphatic histiocytosis is a rare cutaneous condition reported by O’Grady et al¹ in 1994. This condition has been most frequently associated with rheumatoid arthritis²; however, there has been an emerging association in patients with orthopedic metal implants, with and without a concomitant diagnosis of rheumatoid arthritis. Cases associated with metal implants are rare.^2-7

The condition presents as asymptomatic red, brown, or violaceous patches, plaques, papules, or nodules that are ill defined and tend to demonstrate a livedo reticularis–like pattern. The lesions typically are overlying or in close proximity to a joint. Histopathologic findings include dilated vascular structures in the reticular dermis, some with empty lumina and others containing collections of mononuclear histiocytes. There also may be an inflammatory infiltrate in the adjacent dermis composed of a mix of lymphocytes, plasma cells, and/or histiocytes. Endothelial cells lining the dilated lumina express immunoreactivity for CD31, CD34, D2-40, Lyve-1, and Prox-1. Intravascular histiocytes are positive for CD68 and CD31.⁶

The pathogenesis of intralymphatic histiocytosis remains undefined. Some hypothesize that intralymphatic histiocytosis could be the early stage of reactive angioendotheliomatosis, as these conditions share clinical and histological features.⁸ Reactive angioendotheliomatosis also is a rare condition that may present as erythematous to violaceous patches or plaques. The lesions are commonly found on the limbs and may be associated with constitutional symptoms. Histologic findings of reactive angioendotheliomatosis include a proliferation of epithelioid, round, or spindle-shaped cells within the lumina of dermal blood vessels, which show positivity for CD31 and CD34.⁹ Others suggest the lesions of intralymphatic histiocytosis arise from lymphangiectasia; obstruction of lymphatic drainage due to congenital abnormalities; or acquired damage from infection, trauma, surgery, or radiation.² Due to the common association with rheumatoid arthritis and orthopedic implants, it is likely that lymphatic stasis secondary to chronic inflammation plays a notable role.

Therapies such as topical and systemic corticosteroids, local radiotherapy, cyclophosphamide, pentoxifylline, and arthrocentesis have been attempted without evidence of efficacy.² Although intralymphatic histiocytosis is chronic and resistant to therapy, patients can be reassured that the condition runs a benign course.

To the Editor:
Lichen sclerosus (LS) is a chronic inflammatory disorder of unknown etiology that most commonly affects the anogenital region. Progressive sclerosis results in scarring with distortion of the normal epithelial architecture.^1,2 The lifetime risk for developing squamous cell carcinoma (SCC) as a complication of long-standing LS has been estimated as 4% to 6%.^3,4 However, there is no general agreement concerning the exact relationship between anogenital LS and SCC.¹ The coexistence of histologic findings of LS, vulvar intraepithelial neoplasia (VIN), and SCC in the same tissue is rare. We report a case of VIN and SCC developing in a region of preexisting LS.

A 76-year-old woman presented with a 7-mm nodule on the clitoris that was surrounded by a pearly white, smooth, glistening area (Figure 1). The patient reported pain and tenderness associated with the nodule. No regional lymphadenopathy was evident. We performed an excisional biopsy of the entire nodule and a small part of the whitish patch (Figure 2A). On histologic examination, the presence of hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was consistent with LS (Figure 2B). The presence of dysplastic changes with mild disturbance of the epithelial architecture as well as acanthosis and dyskeratosis in the same tissue confirmed VIN (Figure 2C). Dermal invasion and transition to SCC were seen in the part of the tissue verified as VIN. The presence of dermal tumor nests and an irregular border between the epidermis and dermis pointed to the existence of fully developed SCC (Figure 2D). To prevent the recurrence of SCC, the patient returned for follow-up periodically. There was no recurrence within 6 months after excision.

Figure 2. An excisional biopsy showed epidermal thinning on the left side and invasion of the dermis by a tumor nest on the right side (A)(H&E, original magnification ×10). Left, center, and right boxes indicate areas shown in Figures 2B, 2C and 2D, respectively. Hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was evident (B)(H&E, original magnification ×200). Dysplactic changes with mild disturbance of the epithelial architecture accompanied by acanthosis and nuclear atypia were seen (C)(H&E, original magnification ×200). Irregular masses of atypical squamous cells spread downward into the dermis representing squamous cell carcinoma of a well-differentiated type (D)(H&E, original magnification ×200).

Although LS is considered a premalignant condition, only a small portion of patients with LS ultimately develop vulvar SCC.⁵ There are a number of reasons for linking LS with the development of vulvar SCC. First, in the majority of cases of vulvar SCC, LS, squamous cell hyperplasia, or VIN is present in the adjacent epithelium. Lichen sclerosus is found in adjacent regions in up to 62% of vulvar SCC cases.⁶ Second, patients with LS may develop vulvar SCC, as frequently reported. Third, in a series of LS patients who underwent long-term follow-up, 4% to 6% were reported to have developed vulvar SCC.^3,4,7

Lichen sclerosus is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis.² Changes in the local environment of the keratinocyte, including chronic inflammation and sclerosis, may be responsible for the promotion of carcinogenesis.⁸ However, no molecular markers have been proven to identify the LS lesions that are at risk for developing into vulvar SCC.^9,10 It has been suggested that VIN is the direct precursor of vulvar SCC.^11,12

Histologic diagnosis of VIN is difficult. Its identification is hindered by a high degree of cellular differentiation combined with the absence of widespread architectural disorder, nuclear pleomorphism, and diffuse nuclear atypia.¹³ The atypia in VIN lesions is strictly confined to the basal and parabasal layers of the epithelium.¹¹ Vulvar intraepithelial neoplasia has seldom been diagnosed as a solitary lesion because it appears to have a short intraepithelial lifetime.

Vulvar SCC can be divided into 2 patterns. The first is found in older women, which is unrelated to human papillomavirus (HPV). This type occurs in a background of LS and/or differentiated VIN. The second is predominantly found in younger women, which is related to high-risk HPV. This type of vulvar SCC frequently is associated with the histologic subtypes of warty and basaloid differentiations and is referred to as undifferentiated VIN. There is no association with LS in these cases.^2,14,15

It has been suggested that LS and HPV may not be mutually exclusive but may act as cofactors in SCC pathogenesis.¹⁶ Infection with HPV is an early event in the multistep process of vulvar carcinogenesis, and HPV integration into host cell genome seems to be related to the progression of vulvar dysplasia.¹⁷ Viral integration generally disrupts the E2 region, resulting in enhanced expression of E6 and E7. E6 and E7 have the ability to bind and inactivate the protein p53 and retinoblastoma protein, which promotes rapid progression through the cell cycle without p53-mediated control of DNA integrity.¹⁸ However, the exact influence of HPV in vulvar SCC is uncertain, as divergent prevalence rates have been published.

In our case, histologic examination revealed the characteristic findings of LS, VIN, and SCC in succession. This sequence is evidence of progressive transition from LS to VIN and then to SCC. Consequently, this case suggests that vulvar LS may act as both an initiator and a promoter of carcinogenesis and that VIN may be the direct precursor of vulvar SCC. In conclusion, LS has a considerable risk for malignant transformation and requires continuous follow-up in all patients. Early histological detection of invasive lesions is crucial to reduce the risk for vulvar cancer.

To the Editor:
Lichen sclerosus (LS) is a chronic inflammatory disorder of unknown etiology that most commonly affects the anogenital region. Progressive sclerosis results in scarring with distortion of the normal epithelial architecture.^1,2 The lifetime risk for developing squamous cell carcinoma (SCC) as a complication of long-standing LS has been estimated as 4% to 6%.^3,4 However, there is no general agreement concerning the exact relationship between anogenital LS and SCC.¹ The coexistence of histologic findings of LS, vulvar intraepithelial neoplasia (VIN), and SCC in the same tissue is rare. We report a case of VIN and SCC developing in a region of preexisting LS.

A 76-year-old woman presented with a 7-mm nodule on the clitoris that was surrounded by a pearly white, smooth, glistening area (Figure 1). The patient reported pain and tenderness associated with the nodule. No regional lymphadenopathy was evident. We performed an excisional biopsy of the entire nodule and a small part of the whitish patch (Figure 2A). On histologic examination, the presence of hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was consistent with LS (Figure 2B). The presence of dysplastic changes with mild disturbance of the epithelial architecture as well as acanthosis and dyskeratosis in the same tissue confirmed VIN (Figure 2C). Dermal invasion and transition to SCC were seen in the part of the tissue verified as VIN. The presence of dermal tumor nests and an irregular border between the epidermis and dermis pointed to the existence of fully developed SCC (Figure 2D). To prevent the recurrence of SCC, the patient returned for follow-up periodically. There was no recurrence within 6 months after excision.

Figure 2. An excisional biopsy showed epidermal thinning on the left side and invasion of the dermis by a tumor nest on the right side (A)(H&E, original magnification ×10). Left, center, and right boxes indicate areas shown in Figures 2B, 2C and 2D, respectively. Hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was evident (B)(H&E, original magnification ×200). Dysplactic changes with mild disturbance of the epithelial architecture accompanied by acanthosis and nuclear atypia were seen (C)(H&E, original magnification ×200). Irregular masses of atypical squamous cells spread downward into the dermis representing squamous cell carcinoma of a well-differentiated type (D)(H&E, original magnification ×200).

Although LS is considered a premalignant condition, only a small portion of patients with LS ultimately develop vulvar SCC.⁵ There are a number of reasons for linking LS with the development of vulvar SCC. First, in the majority of cases of vulvar SCC, LS, squamous cell hyperplasia, or VIN is present in the adjacent epithelium. Lichen sclerosus is found in adjacent regions in up to 62% of vulvar SCC cases.⁶ Second, patients with LS may develop vulvar SCC, as frequently reported. Third, in a series of LS patients who underwent long-term follow-up, 4% to 6% were reported to have developed vulvar SCC.^3,4,7

Lichen sclerosus is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis.² Changes in the local environment of the keratinocyte, including chronic inflammation and sclerosis, may be responsible for the promotion of carcinogenesis.⁸ However, no molecular markers have been proven to identify the LS lesions that are at risk for developing into vulvar SCC.^9,10 It has been suggested that VIN is the direct precursor of vulvar SCC.^11,12

Histologic diagnosis of VIN is difficult. Its identification is hindered by a high degree of cellular differentiation combined with the absence of widespread architectural disorder, nuclear pleomorphism, and diffuse nuclear atypia.¹³ The atypia in VIN lesions is strictly confined to the basal and parabasal layers of the epithelium.¹¹ Vulvar intraepithelial neoplasia has seldom been diagnosed as a solitary lesion because it appears to have a short intraepithelial lifetime.

Vulvar SCC can be divided into 2 patterns. The first is found in older women, which is unrelated to human papillomavirus (HPV). This type occurs in a background of LS and/or differentiated VIN. The second is predominantly found in younger women, which is related to high-risk HPV. This type of vulvar SCC frequently is associated with the histologic subtypes of warty and basaloid differentiations and is referred to as undifferentiated VIN. There is no association with LS in these cases.^2,14,15

It has been suggested that LS and HPV may not be mutually exclusive but may act as cofactors in SCC pathogenesis.¹⁶ Infection with HPV is an early event in the multistep process of vulvar carcinogenesis, and HPV integration into host cell genome seems to be related to the progression of vulvar dysplasia.¹⁷ Viral integration generally disrupts the E2 region, resulting in enhanced expression of E6 and E7. E6 and E7 have the ability to bind and inactivate the protein p53 and retinoblastoma protein, which promotes rapid progression through the cell cycle without p53-mediated control of DNA integrity.¹⁸ However, the exact influence of HPV in vulvar SCC is uncertain, as divergent prevalence rates have been published.

In our case, histologic examination revealed the characteristic findings of LS, VIN, and SCC in succession. This sequence is evidence of progressive transition from LS to VIN and then to SCC. Consequently, this case suggests that vulvar LS may act as both an initiator and a promoter of carcinogenesis and that VIN may be the direct precursor of vulvar SCC. In conclusion, LS has a considerable risk for malignant transformation and requires continuous follow-up in all patients. Early histological detection of invasive lesions is crucial to reduce the risk for vulvar cancer.

To the Editor:
Lichen sclerosus (LS) is a chronic inflammatory disorder of unknown etiology that most commonly affects the anogenital region. Progressive sclerosis results in scarring with distortion of the normal epithelial architecture.^1,2 The lifetime risk for developing squamous cell carcinoma (SCC) as a complication of long-standing LS has been estimated as 4% to 6%.^3,4 However, there is no general agreement concerning the exact relationship between anogenital LS and SCC.¹ The coexistence of histologic findings of LS, vulvar intraepithelial neoplasia (VIN), and SCC in the same tissue is rare. We report a case of VIN and SCC developing in a region of preexisting LS.

A 76-year-old woman presented with a 7-mm nodule on the clitoris that was surrounded by a pearly white, smooth, glistening area (Figure 1). The patient reported pain and tenderness associated with the nodule. No regional lymphadenopathy was evident. We performed an excisional biopsy of the entire nodule and a small part of the whitish patch (Figure 2A). On histologic examination, the presence of hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was consistent with LS (Figure 2B). The presence of dysplastic changes with mild disturbance of the epithelial architecture as well as acanthosis and dyskeratosis in the same tissue confirmed VIN (Figure 2C). Dermal invasion and transition to SCC were seen in the part of the tissue verified as VIN. The presence of dermal tumor nests and an irregular border between the epidermis and dermis pointed to the existence of fully developed SCC (Figure 2D). To prevent the recurrence of SCC, the patient returned for follow-up periodically. There was no recurrence within 6 months after excision.

Figure 2. An excisional biopsy showed epidermal thinning on the left side and invasion of the dermis by a tumor nest on the right side (A)(H&E, original magnification ×10). Left, center, and right boxes indicate areas shown in Figures 2B, 2C and 2D, respectively. Hyperkeratosis, epidermal atrophy, a swollen dermal collagen bundle, and prominent edema was evident (B)(H&E, original magnification ×200). Dysplactic changes with mild disturbance of the epithelial architecture accompanied by acanthosis and nuclear atypia were seen (C)(H&E, original magnification ×200). Irregular masses of atypical squamous cells spread downward into the dermis representing squamous cell carcinoma of a well-differentiated type (D)(H&E, original magnification ×200).

Although LS is considered a premalignant condition, only a small portion of patients with LS ultimately develop vulvar SCC.⁵ There are a number of reasons for linking LS with the development of vulvar SCC. First, in the majority of cases of vulvar SCC, LS, squamous cell hyperplasia, or VIN is present in the adjacent epithelium. Lichen sclerosus is found in adjacent regions in up to 62% of vulvar SCC cases.⁶ Second, patients with LS may develop vulvar SCC, as frequently reported. Third, in a series of LS patients who underwent long-term follow-up, 4% to 6% were reported to have developed vulvar SCC.^3,4,7

Lichen sclerosus is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis.² Changes in the local environment of the keratinocyte, including chronic inflammation and sclerosis, may be responsible for the promotion of carcinogenesis.⁸ However, no molecular markers have been proven to identify the LS lesions that are at risk for developing into vulvar SCC.^9,10 It has been suggested that VIN is the direct precursor of vulvar SCC.^11,12

Histologic diagnosis of VIN is difficult. Its identification is hindered by a high degree of cellular differentiation combined with the absence of widespread architectural disorder, nuclear pleomorphism, and diffuse nuclear atypia.¹³ The atypia in VIN lesions is strictly confined to the basal and parabasal layers of the epithelium.¹¹ Vulvar intraepithelial neoplasia has seldom been diagnosed as a solitary lesion because it appears to have a short intraepithelial lifetime.

Vulvar SCC can be divided into 2 patterns. The first is found in older women, which is unrelated to human papillomavirus (HPV). This type occurs in a background of LS and/or differentiated VIN. The second is predominantly found in younger women, which is related to high-risk HPV. This type of vulvar SCC frequently is associated with the histologic subtypes of warty and basaloid differentiations and is referred to as undifferentiated VIN. There is no association with LS in these cases.^2,14,15

It has been suggested that LS and HPV may not be mutually exclusive but may act as cofactors in SCC pathogenesis.¹⁶ Infection with HPV is an early event in the multistep process of vulvar carcinogenesis, and HPV integration into host cell genome seems to be related to the progression of vulvar dysplasia.¹⁷ Viral integration generally disrupts the E2 region, resulting in enhanced expression of E6 and E7. E6 and E7 have the ability to bind and inactivate the protein p53 and retinoblastoma protein, which promotes rapid progression through the cell cycle without p53-mediated control of DNA integrity.¹⁸ However, the exact influence of HPV in vulvar SCC is uncertain, as divergent prevalence rates have been published.

In our case, histologic examination revealed the characteristic findings of LS, VIN, and SCC in succession. This sequence is evidence of progressive transition from LS to VIN and then to SCC. Consequently, this case suggests that vulvar LS may act as both an initiator and a promoter of carcinogenesis and that VIN may be the direct precursor of vulvar SCC. In conclusion, LS has a considerable risk for malignant transformation and requires continuous follow-up in all patients. Early histological detection of invasive lesions is crucial to reduce the risk for vulvar cancer.

The Diagnosis: Congenital Folliculosebaceous Cystic Hamartoma

Folliculosebaceous cystic hamartoma (FSCH) is a rare skin condition that is either congenital or acquired. It presents as a slow-growing and flesh-colored papulonodular lesion¹ that mainly occurs on the head and neck. Involvement of the nipples, perineum, back, forearms, genital areas, and subcutaneous tissue also has been reported but usually indicates a larger lesion.^1,2

Histologically, FSCH is considered a hamartoma composed of both ectodermal and mesodermal elements.¹ Folliculosebaceous cystic hamartoma is a more complex lesion composed of infundibulocystic structures connected to maloriented folliculosebaceous units surrounded by whorls of highly vascularized fibrous stroma and adipocytes. Clefts between fibroepithelial units and surrounding stroma usually are present.¹

Epithelial components contribute to the adnexal and folliculosebaceous cystic proliferations, and mesenchymal elements include vascular tissue, adipose tissue, and fibroblast-rich stroma.^1,2 Acquired lesions arising in adults have been described,^1-5 but the congenital presentation of FSCH in infancy is rare.

Histopathologically, some variations of FSCH are mainly composed of epithelial components while others are composed of nonepithelial components. Nonepithelial components include neural proliferation, muscle components, vascular proliferation, and mucin deposition.^1-4 In some cases, FSCH may coexist with other diseases, such as nevus lipomatosus cutaneous superficialis and neurofibromatosis type I.^4,5

In our case, histopathology showed several dermal infundibulocystic structures that were lined by stratified squamous epithelium and contained horny material (Figure 1). Numerous immature sebaceous lobules and rudimentary hair follicles emanated from some of the cyst walls. Mesenchymal changes around the fibroepithelial units included fibrillary bundles of collagen, clusters of adipocytes, and an increased number of small venules (Figure 2). In addition, the stroma adjacent to the malformed perifollicle contained some amount of mucin. Prominent clefts formed between fibroepithelial units and the surrounding altered stroma.
 

The differential diagnosis mainly includes sebaceous trichofolliculoma, molluscum contagiosum, dermoid cysts, pilomatrixoma, Spitz nevus, and nevus lipomatosus superficialis. The differential diagnosis between FSCH and sebaceous trichofolliculoma is challenging. Both lesions show an infundibular cyst and surrounding sebaceous nodules. According to Plewig,⁶ trichofolliculoma has a wide spectrum ranging from low to high differentiation represented by trichofolliculoma, sebaceous trichofolliculoma, and FSCH, respectively. It is not difficult to distinguish FSCH from other diseases according to its peculiar histopathologic features.

The clinicopathologic features of our case were similar to those of reported FSCH cases, except for the following unique characteristics: congenital lesion, lack of terminal hair, and no sebaceous material extrusion. These features of hair and sebaceous material may be correlated with the patient’s age and hormonal level.¹ Androgen may play a key role in sebaceous gland development at puberty, which leads to sebaceous gland hyperplasia and hypertrophy. Therefore, slight pressure from the lesions can make ivory-white sebaceous material discharge. Hence, the dermatologist and pediatrician must be poised and sensitive while making an initial diagnosis of FSCH.

The Diagnosis: Congenital Folliculosebaceous Cystic Hamartoma

Folliculosebaceous cystic hamartoma (FSCH) is a rare skin condition that is either congenital or acquired. It presents as a slow-growing and flesh-colored papulonodular lesion¹ that mainly occurs on the head and neck. Involvement of the nipples, perineum, back, forearms, genital areas, and subcutaneous tissue also has been reported but usually indicates a larger lesion.^1,2

Histologically, FSCH is considered a hamartoma composed of both ectodermal and mesodermal elements.¹ Folliculosebaceous cystic hamartoma is a more complex lesion composed of infundibulocystic structures connected to maloriented folliculosebaceous units surrounded by whorls of highly vascularized fibrous stroma and adipocytes. Clefts between fibroepithelial units and surrounding stroma usually are present.¹

Epithelial components contribute to the adnexal and folliculosebaceous cystic proliferations, and mesenchymal elements include vascular tissue, adipose tissue, and fibroblast-rich stroma.^1,2 Acquired lesions arising in adults have been described,^1-5 but the congenital presentation of FSCH in infancy is rare.

Histopathologically, some variations of FSCH are mainly composed of epithelial components while others are composed of nonepithelial components. Nonepithelial components include neural proliferation, muscle components, vascular proliferation, and mucin deposition.^1-4 In some cases, FSCH may coexist with other diseases, such as nevus lipomatosus cutaneous superficialis and neurofibromatosis type I.^4,5

In our case, histopathology showed several dermal infundibulocystic structures that were lined by stratified squamous epithelium and contained horny material (Figure 1). Numerous immature sebaceous lobules and rudimentary hair follicles emanated from some of the cyst walls. Mesenchymal changes around the fibroepithelial units included fibrillary bundles of collagen, clusters of adipocytes, and an increased number of small venules (Figure 2). In addition, the stroma adjacent to the malformed perifollicle contained some amount of mucin. Prominent clefts formed between fibroepithelial units and the surrounding altered stroma.
 

The differential diagnosis mainly includes sebaceous trichofolliculoma, molluscum contagiosum, dermoid cysts, pilomatrixoma, Spitz nevus, and nevus lipomatosus superficialis. The differential diagnosis between FSCH and sebaceous trichofolliculoma is challenging. Both lesions show an infundibular cyst and surrounding sebaceous nodules. According to Plewig,⁶ trichofolliculoma has a wide spectrum ranging from low to high differentiation represented by trichofolliculoma, sebaceous trichofolliculoma, and FSCH, respectively. It is not difficult to distinguish FSCH from other diseases according to its peculiar histopathologic features.

The clinicopathologic features of our case were similar to those of reported FSCH cases, except for the following unique characteristics: congenital lesion, lack of terminal hair, and no sebaceous material extrusion. These features of hair and sebaceous material may be correlated with the patient’s age and hormonal level.¹ Androgen may play a key role in sebaceous gland development at puberty, which leads to sebaceous gland hyperplasia and hypertrophy. Therefore, slight pressure from the lesions can make ivory-white sebaceous material discharge. Hence, the dermatologist and pediatrician must be poised and sensitive while making an initial diagnosis of FSCH.

The Diagnosis: Congenital Folliculosebaceous Cystic Hamartoma

Folliculosebaceous cystic hamartoma (FSCH) is a rare skin condition that is either congenital or acquired. It presents as a slow-growing and flesh-colored papulonodular lesion¹ that mainly occurs on the head and neck. Involvement of the nipples, perineum, back, forearms, genital areas, and subcutaneous tissue also has been reported but usually indicates a larger lesion.^1,2

Histologically, FSCH is considered a hamartoma composed of both ectodermal and mesodermal elements.¹ Folliculosebaceous cystic hamartoma is a more complex lesion composed of infundibulocystic structures connected to maloriented folliculosebaceous units surrounded by whorls of highly vascularized fibrous stroma and adipocytes. Clefts between fibroepithelial units and surrounding stroma usually are present.¹

Epithelial components contribute to the adnexal and folliculosebaceous cystic proliferations, and mesenchymal elements include vascular tissue, adipose tissue, and fibroblast-rich stroma.^1,2 Acquired lesions arising in adults have been described,^1-5 but the congenital presentation of FSCH in infancy is rare.

Histopathologically, some variations of FSCH are mainly composed of epithelial components while others are composed of nonepithelial components. Nonepithelial components include neural proliferation, muscle components, vascular proliferation, and mucin deposition.^1-4 In some cases, FSCH may coexist with other diseases, such as nevus lipomatosus cutaneous superficialis and neurofibromatosis type I.^4,5

In our case, histopathology showed several dermal infundibulocystic structures that were lined by stratified squamous epithelium and contained horny material (Figure 1). Numerous immature sebaceous lobules and rudimentary hair follicles emanated from some of the cyst walls. Mesenchymal changes around the fibroepithelial units included fibrillary bundles of collagen, clusters of adipocytes, and an increased number of small venules (Figure 2). In addition, the stroma adjacent to the malformed perifollicle contained some amount of mucin. Prominent clefts formed between fibroepithelial units and the surrounding altered stroma.
 

The differential diagnosis mainly includes sebaceous trichofolliculoma, molluscum contagiosum, dermoid cysts, pilomatrixoma, Spitz nevus, and nevus lipomatosus superficialis. The differential diagnosis between FSCH and sebaceous trichofolliculoma is challenging. Both lesions show an infundibular cyst and surrounding sebaceous nodules. According to Plewig,⁶ trichofolliculoma has a wide spectrum ranging from low to high differentiation represented by trichofolliculoma, sebaceous trichofolliculoma, and FSCH, respectively. It is not difficult to distinguish FSCH from other diseases according to its peculiar histopathologic features.

The clinicopathologic features of our case were similar to those of reported FSCH cases, except for the following unique characteristics: congenital lesion, lack of terminal hair, and no sebaceous material extrusion. These features of hair and sebaceous material may be correlated with the patient’s age and hormonal level.¹ Androgen may play a key role in sebaceous gland development at puberty, which leads to sebaceous gland hyperplasia and hypertrophy. Therefore, slight pressure from the lesions can make ivory-white sebaceous material discharge. Hence, the dermatologist and pediatrician must be poised and sensitive while making an initial diagnosis of FSCH.